Receptor Tyrosine Kinase Inhibitors in Cancer Immunotherapy

doi:10.21203/rs.3.rs-2251865/v1

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Receptor Tyrosine Kinase Inhibitors in Cancer Immunotherapy

https://doi.org/10.21203/rs.3.rs-2251865/v1

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published 22 Mar, 2023

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Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) that have entered clinical applications. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy drugs with one RTKI or multiple RTKIs) especially for drug resistant cancers.

Targeted therapy

Cancer

Receptor tyrosine kinases

RTK inhibitors

Drug resistance

Cancer describes a variety of diseases which can affect any part of the body, characterized by the rapid growth of abnormal cells beyond their normal boundaries and which can invade other organs (1). According to the International Agency for Research on Cancer (IARC) GLOBOCAN statistics, data from 185 countries reported about 19.3 million cancers and 10 million deaths worldwide (2). Distant metastasis is the leading cause of cancer-related death. Overall, liver, lung, and gastric cancers were the most common cause of cancer death (2, 3).

Combination therapies, including chemotherapy plus surgery or radiotherapy, are the most common treatment options (4). Various types of chemotherapy drugs can be used depending on the cancer type and stage. The majority of tumors become resistant to chemotherapy following mutations in the target proteins, or secondary changes in the target pathway that bypass the site of action, and thus the treatment fails (5). Targeted therapy is a new treatment approach, involving strategies that target characteristic traits in the cells/proteins which promote cancer progression. Targeted therapy uses a drug designed to repress a specific key molecule that is involved in maintaining the growth and proliferation of cancer cells, and thus inhibits tumor progression (4, 6, 7).

Signal transduction mediates cell-to-cell communication as a pathway by which an external signal (biological, physical, electrical, or chemical) triggers a response in the cells following binding of an extracellular factor to a receptor. This binding activates a protein kinase in the intracellular region, and consequently triggers a series of biochemical events (8). Receptor tyrosine kinases (RTKs) are a group of transmembrane receptors characterized by the inherent activity of a tyrosine kinase (TK) in their cytoplasmic region. RTKs are expressed in body tissues of multicellular animals during both prenatal and postnatal development, and have an important role in cell survival, proliferation, differentiation, metabolism, regeneration, and cell death pathways (7, 9). In the last decade, new methods such as molecular targeting of RTKs have been shown to improve treatment outcomes for cancer patients. Many investigations have shown that RTK dysfunction is involved in different human diseases, especially cancer (4, 6).

A better understanding of RTKs, their signaling pathways, and the effects of RTKs on cellular functions has enabled the development of many targeted drug therapies, along with improved clinical outcomes (9, 10). This review article discusses the current RTK-targeted therapies available for cancer patients.

RTK are a type of membrane-bound protein usually activated by the binding of receptor-specific ligands. Their intrinsic catalytic activity allows the phosphorylation of tyrosine residues. It is triggered by the binding of a ligand to the extracellular domain of the RTK protein that helps to stabilize the activation state (8, 11). The RTK superfamily now has 58 members which are divided into 20 subfamilies/classes (Table 1) (12, 13). All RTKs have a similar structure which includes an extracellular ligand-binding domain, a transmembrane α-helix spanning the cell membrane, an intracellular tyrosine kinase domain (TKD), a cytoplasmic juxtamembrane regulatory region, and a carboxy (C)-terminus tail (14). The extracellular ligand-binding domain varies according to the receptor subfamily. For most RTKs, the specific ligand is a soluble factor, such as growth factors, cytokines, hormones etc. (8, 12).

Table 1

The classification of RTKs subfamilies
Class	Subfamily name	Members
1	EGFR	EGFR, ERBB2/3/4
2	Ins	INSR IGFR
3	PDGF	PDGFRα, PDGFRβ, M-CSFR, KIT, FLT3L
4	VEGF	VEGFR1/2/3
5	FGFs	FGFR1/2/3/4
6	CCK	CCK4
7	NGF	TRKA, TRKB, TRKC
8	HGF	RON, MET
9	Eph	EPHA1-6, EPHB1-6
10	AXL	AXL, MER, TYRO3
11	TIE	TIE, TEK
12	RYK	RYK
13	DDRs	DDR1/2
14	RET	RET
15	ROS	ROS
16	LTK	ALK, LTK
17	ROR	ROR1/2
18	MuSK	MuSK
19	LMR	AATYK1/2/3
20	Undetermined	Undetermined
* EGFR, Epidermal growth factor receptor; InsR, Insulin receptor; PDGFR, Platelet-derived growth factor receptor; VEGFR, Vascular endothelial growth factor receptor; FGFR, Fibroblast growth factor receptor; CCK, Colon carcinoma kinase; NGFR, Nerve growth factor receptor; HGFR, Hepatocyte growth factor receptor; EphR, Ephrin receptor; Axl, a Tyro3 PTK; TIE, Tyrosine kinase receptor in endothelial cells; RYK, Receptor related to tyrosine kinases; DDR, Discoidin domain receptor; Ret, Rearranged during transfection; ROS, RPTK expressed in some epithelial cell types; LTK, Leukocyte tyrosine kinase; ROR, Receptor orphan; MuSK, Muscle-specific kinase; LMR, Lemur.

The enzymatic activity of RTKs includes, phosphatidylinositol 3ʹ-kinase (PI3K), phospholipase Cγ, and cytoplasmic TKs of the Src superfamily. Moreover, some proteins without enzymatic activity such as scaffold and adaptor proteins have roles as signaling proteins in recruiting and assembling the RTK via additional protein-protein interaction domains (15). Adaptor proteins and protein kinases contain Src homology 2 (SH2), SH3, and phosphotyrosine-binding (PTB) domains which mediate the phosphotyrosine binding and polyproline region activation. These play significant roles in signaling pathway cascades and activation of other protein kinases (8, 16). In addition, RTKs can use other signaling pathways, such as PI3K/V-Akt murine thymoma viral oncogene homolog (Akt), mammalian target of rapamycin (mTOR), phospholipase C gamma 1 or protein kinase C (PLCG1/PKC), and mitogen-activated protein kinase or extracellular signal-regulated kinase (MAPK/ERK).

These signaling cascades alter the transcription of genes and produce non-transcriptional alterations that strengthen the cytoskeletal machinery for cell deformation, adhesion, motility, cell differentiation and progression, and can prevent cellular apoptosis (15, 17). It should be noted that RTK signaling can occur inside endosomes and also at the surface of cells, involving diverse signaling pathways dependent on the receptor location. In general, the binding of secreted ligands to the RTK extracellular domain can cause three structural changes, including ligand-induced homo- or heterodimerization of the receptor, the cytoplasmic kinase domain activation leading to tyrosine phosphorylation, and activation of multiple intracellular signaling cascades (Fig. 1) (18).

Ligand-induced homo- or heterodimerization of the receptor

Preliminary studies on RTKs have shown that these receptors are present at the cell surface as monomers, while the reponse to ligand binding involves two monomers converting into an active dimer. Later reports have shown that certain RTKs can exist as dimers (such as Ins) or as oligomers (such as EGFR) on the cell surface before ligand binding. In addition, some RTKs require oligomers to become activated instead of dimers (such as TIE2, Eph). The ligand binding then stimulates tyrosine kinase activity (19, 20).

The dimerization of RTKs can either be ligand-mediated; e.g. TIE2, TRKA, mast/stem cell growth factor receptor kit (c-KIT), and VEGF-R1/FMS related receptor tyrosine kinase 1 (Flt1), or else receptor-mediated; e.g., EGFR family (17). In the first case, the two RTK monomers within the cell membrane are not in contact with each other, and the binding of the ligand makes them come togther. In the second case, the ligand does not form part of the dimer interface, and the binding of the ligand to each receptor monomer causes structural changes in the extracellular domain and exposes sites for dimerization. There are cases where the dimer junction is formed by both the extracellular receptor region and the ligand, and other cases where the dimer interface is formed by interactions between the receptors, ligand, and an auxiliary molecule (e.g. heparin in the FGFR family) (8, 20).

Activation of the cytoplasmic kinase domains and tyrosine phosphorylation

For activation of the TKDs of RTKs, the N-lobe alpha-C helix and activation loop of TKDs must adopt a specific "active" configuration. It has been pointed out that cis-autoinhibition is necessary for this to happen, which occurs by different mechanisms (21).

In TIR2 and insulin RTKs, tyrosine residues on the C-terminal tail or the activation loop settle into the kinase active site, respectively. This region containing tyrosine autophosphorylation sites blocks the binding of the substrate to the active site, in a type of cis-inhibition mechanism (17). Tyrosines interact with the TKD and its activation loop in some RTKs, including Flt3, c-KIT, Eph family, and MuSK, in the juxtamembrane region, fixing it in an inactive conformation through juxtamembrane autoinhibition (17). It has been shown that some mutations in the juxtamembrane autoinhibition mechanism of the KIT/PDGFR family are often associated with some cancers (22). In all types, ligand-induced dimerization allows the release of the cis-autoinhibition, and therefore permits RTK activity (17).

Some RTKs such as the EGFR/ErbB and RET family are an exception to this rule because they do not require transphosphorylation for activation (23, 24). The maintenance of EGFR in a non-active conformation is mediated by allosteric interactions within the N-lobe of the TKD of an RTK monomer. However, these interactions are interrupted by the C-lobe of TKD of another RTK monomer after dimerization, leading to the activation of the TKD receptor. The activation mechanism of these TKDs is not completely understood. It has been theorized that RET may act as a trans-inhibited dimer, and following ligand binding the inhibitory interactions are reduced (8, 23).

Activation of multiple intracellular signaling cascades

The trans-autophosphorylation pathway is involved in the ability of RTKs to modulate cellular signaling pathways, except for EGFR and RET. In general, autophosphorylation is carried out in two steps. In the first step, trans-autophosphorylation of tyrosine residues reduces the cis-autoinhibition and allows the TKD to adopt an active configuration and to optimize enzyme kinetics. In the second step, additional tyrosines are phosphorylated in the C-terminal tail, juxtamembrane region, and TKD, forming phosphotyrosine binding sites which can interact with SH2 or PTB domain adapter kinases and proteins. It has also been suggested that TKD may phosphorylate tyrosines on related docking proteins that lack enzymatic activity themselves, but may provide additional binding sites (17).

The biological consequences of these cellular pathways and related RTKs are essential not only in prenatal development, but also for the function of mature tissues and postnatal homeostasis. For instance, AXL and Mer (AXL subfamily receptor) suppress the immune system by inhibiting the production of TLR-induced cytokines and also enhance the phagocytic uptake of apoptotic cells. VEGF and PDGF receptors stimulate angiogenesis, vascular remodeling, regulate vasculogenesis, and fibroblast-induced collagen synthesis to accelerate wound healing. It has been reported that mouse embryos with disruption of these signaling pathways undergo death due to abnormal vascular formation and cardiac dysfunction (25). RET/GDNF (glial cell-line derived neurotrophic factor) signaling is essential for organ development, such as kidneys, intestinal nervous system, neuroblastoma tissues, and ureters. Studies have shown that the RET knock-out mutants showed abnormalities in renal and ureteral formation. Nevertheless, RET mutations only occurred in a small percentage, indicating that these mutations are not critical (26–28). MuSK is expressed on skeletal muscle cells involved in neuromuscular junction formation and clustering of acetylcholine receptors, and enhances the expression of genes encoding synaptic proteins. The Ins receptor modulates glycogenesis, glucose homeostasis, and lipogenesis in body fat. TrkA/TrkB/TrkC receptors (neural growth factor/brain-derived neurotrophic factor/neurotrophin-3 receptors) and TAM family receptors (e.g. Tyro3, Axl, and MerTK) are necessary for the survival of neurons, as well as the development and function of the central nervous system. These receptors increase the survival and growth of motor neurons and axons (29, 30). In addition, MerTK and/or Axl expression is associated with increased cancer cell survival, lymph node metastasis, drug resistance, and tumor development in several solid and hematological cancers, including acute myeloid leukemia, non-small-cell lung cancer (NSCLC), breast, liver, and gastric cancer (31, 32). c-KIT/SCF is involved in spermatogenesis, and leads to overexpression of EphA2 in human breast cancer (33). TIE2/angiopoietin-1 (ANG1) signaling has an essential role in venous morphogenesis. It also is important for venous healing and maintenance. Tie2 deficiency causes the death of mice due to damaged vascular organization, and in patients with venous malformations, tome TIE2 mutations are often seen (34). EGF receptors (i.e., ErbB1-4) are widely expressed in embryonic tissues and the lack of EGFR can lead to defects in tissues such as skin, CNS, intestines, liver, lungs, peripheral nervous system, and cranial sensory ganglia myelination. It also leads to failure to form cardiac ventricle trabeculae, which results in intrauterine death (35). Many RTK-ligand systems have essential functions in different tissues, and researchers are constantly discovering new roles for them (25, 36–38).

Although the activity of RTKs is strongly controlled in normal cells, these receptors may undergo changes that lead to oncogenic activation, tumor metastasis, angiogenesis, and therapy resistance, due to autocrine or paracrine stimulation, mutations, or overexpression (39, 40). These changes can lead to greater affinity of RTK receptors to their ligands, increased activity of TKD regions, or an increased tendency for dimerization due to the disappearance of cis-inhibitory interactions (41, 42). Generally, increased RTK signaling can occur through several mechanisms, including gain-of-function mutations in RTK genes, DNA amplification of RTK genes (43), or ROS translocations in RTK genes (44). This is associated with uncontrolled cellular proliferation and several hyperproliferative diseases, including cancer (8). About 30% of mutated/overexpressed RTKs have been detected in different human cancers (13). For instance, gain-of-function mutations in FLT3, MET (the mesenchymal-epithelial transcription factor), FGFR3, c-KIT, and RET genes in acute myeloid leukemia, In renal cell carcinoma (RCC), bladder and breast cancer, gastrointestinal stromal tumor, and medullary thyroid cancer RTK activation occurs in a ligand-independent manner along with increased RTK signaling (45–47). In addition, in some other cancers, gain-of-function mutations have been found, such as v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E substitution mutations in papillary thyroid cancer, melanoma, and lung adenocarcinoma. Other examples are: Akt1 E17K point mutations in ovarian, lung, colorectal, and breast cancer; kirsten rat sarcoma (KRAS) mutations in colorectal, pancreatic, thyroid, lung, and ovarian cancer; and PIK3CA mutations in breast, endometrial, colorectal, cervical, and anal cancer (48).

Researchers have detected that changes and mutations in some oncogenic driver genes, including KRAS, EGFR, MET, BRAF, anaplastic lymphoma kinase (ALK), c-ROS oncogene 1, neurotrophic receptor tyrosine kinase (NTRK), HER2/neu2, and neuregulin-1 are associated with NSCLC (49), and suggested that targeting these oncogenes could be a potential therapeutic strategy for the treatment of these patients.

There have been many reports of RTK involvement in various cancers. For instrance, Abdel-Rahman WM, et al. evaluated the expression of AXL RTK in association with tumor protein P53 and its role in tumor metastasis and response to chemotherapy in colon and breast cancer cells. In comparison with AXL-silenced cells, AXL-activated cells, which are affected by p53, increased the invasive potential of cancer cells after exposure to chemotherapy. The silencing of AXL demonstrated a minor trend in restoring colon cancer cell sensitivity to chemotherapy, including irinotecan and fluorouracil (5FU) (50). In addition, it has been shown that the expression of the RET gene encoding RET-RTK has a role in diagnosis and prognosis of medullary thyroid carcinoma (MTC) (51). The c-Met/MET, RTK, is upregulated in many cancers, e.g., NSCLC, colorectal cancer (CRC), gastric cancer, and hepatocellular carcinoma (HCC) (52). Tivantinib, a selective RTK inhibitor targeting the c-Met pathway has been evaluated in advanced Met-positive HCC patients (53). Met binds to HGF to activate intracellular signaling pathways, including MEK, PI3K-Akt, MAPK, STAT3 (signal transducer and activator of transcription 3), beta-catenin, and Notch pathways (54, 55). Tivantinib prevents cell growth by inhibiting Met autoactivation and stabilization of the inactive non-phosphorylated kinase configuration (54).

In a study by Abou-Fayçal C. et al., the role of alternative splicing in cancer growth and RTKs-targeted therapies response was evaluated. The bioactivity of RTK alternative splice forms and the upstream signals controling their expression in cancer was reported. It has been reported that RTK alternative splicing has some biological consequences, for example, the alteration of RTK subcellular distribution and function, the modification of RTK affinity to their ligands, and reprogramming of cells with more invasive characteristics (7).

Recently, researchers have suggested a double-sided role for the TAM receptors (Tyro3, Axl and MerTK) in the pathogenesis of cancers, such as glioblastoma. TAM receptors are overexpressed in several cancers and can play a major role in tumor development, invasion, and treatment resistance by mediating efferocytosis, immune cell regulation, inflammatory factor secretion, and induction of the epithelial-to-mesenchymal transition (EMT) in the tumor microenvironment. On the other hand, an opposing view proposes an anticancer role of TAM receptors by regulating immune cell functions and angiogenesis inhibition under certain circumstances. It has been reported that these differing roles of TAM receptors could be due to the precise cellular conditions, including the inflammation level, the type of cancer, and immune cell function. In many clinical trials of TAM receptor targeted therapy, different treatment outcomes may be seen after targeting one or more TAM receptors. However, combination therapy with TAM receptor inhibitors plus other immunotherapy agents like anti-PD-L1, could be a good approach for TAM-related cancer therapy (56). Such findings have motivated the expansion of RTK inhibitors (RTKIs) in cancer therapy over the past three decades.

As mentioned above, tyrosine kinase proteins are crucial factors in cancer development and are often overexpressed during carcinogenesis. Hence, many investigations have suggested that RTKs could be a new target for molecular cancer treatment (57). In the last three decades, numerous RTK-targeted drugs have been developed, some of which have led to significant clinical advances (Table 2). Diverse approaches have been investigated for inhibiting RTKs, including using antibodies against kinase protein extracellular domains, and antibodies against both transmembrane and intracellular proteins, which can inhibit growth factor binding/ receptor dimerization or TKD phosphorylation. Most small molecule RTKIs target and bind to the enzymatic domain and compete with the ATP binding pocket. The specificity of RTKIs is preserved due to the unique binding pockets (57, 58). The number of small molecule RTKIs is much higher than RTK-targeted monoclonal antibodies. Following inhibition of RTKs, the proliferation of cancer cells is inhibited, and apoptosis is promoted (8).

Table 2

Different RTKIs in numerous cancers treatment
RTKIs	Functions	Cancer type	Reference
Linifanib	Antitumor and antiangiogenic activities through VEGF and PGF receptors inhibition	Liver cancer NSCLC, breast cancer, and CRC Human HCC	(117, 118)
Pazopanib	VEGF receptors, c-Kit protein, and inhibiting angiogenesis	RCC	(119, 120)
Sunitinib	Androgen receptor inhibition and protein phosphorylation	RCC	(121)
Sorafenib	Target RAF/MEK/ERK serine/threonine pathway and RTKs and inhibition of tumor cell growth and angiogenesis	Eruptive keratoacanthomas (Grzybowski syndrome), HCC and advanced RCC	(122, 123)
Trametinib, Crizotinib, or Selpercatinib	CSF1R (M-CSF), MEK1/2, ALK, RET inhibition through mutations in genes encoding RTKs	Histiocytoses (clonal hematopoietic disorders)	(124)
Pexidartinib	Blok the CSF1R and/or KIT proto-oncogene RTK activity	Tenosynovial giant cell tumor	(125)
Trastuzumab, pertuzumab	Inhibition of ERBB2	Breast cancer, HER2-positive metastatic breast cancer	(69, 126)
Neratinib, Afatinib, Dacomitinib	HER2 and ErbB2 inhibition	NSCLC and breast cancer	(127–130)
Benzimidazole derivatives	Inhibition of EGFR	HCC	(131, 132)
Ripretinib, avapritinib	KIT/PDGFRA kinase inhibitors	Gastrointestinal stromal tumors	(133)
Imatinib	Inhibition of PDGF	Pulmonary hypertension and respiratory dysfunction	(134)
Gefitinib, Erlotinib	Target the EGFR	NSCLC	(79)
Lapatinib	Inhibition of EGFR and ErbB-1/-2 receptors; influencing pyruvate kinase type M2 expression	Mammary carcinoma, pancreatic cancer	(88, 135, 136)
Trastuzumab	ErbB2 inhibition	Breast cancer	(68)
Cetuximab	EGFR inhibition	CCR, Squamous cell carcinomas, and Head and Neck Cancer	(137, 138)
Cetuximab, Panitumumab	EGF/EGFR binding inhibition	Metastatic colon cancer	(72)
Bevacizumab	VEGF inhibitor	Lung cancer, CRC	(111)
Ramucirumab	VEGFR-2 inhibitor	Gastric, gastro-oesophageal adenocarcinoma	(75, 76)
Midostaurin	a FLT3 inhibitor	Acute myeloid leukemia, systemic mastocytosis	(92)
Almonertinib	Inhibition the tumor cell EMT and expression of metalloproteinase	NSCLC	(85)
Lenvatinib	Antiangiogenic properties	Thyroid cancer, advanced HCC and RCC	(139)
Tivozanib, nivolumab	VEGF inhibition	RCC	(140)
W2014-S	Disrupted STAT3 dimerization and signaling then suppressed proliferation, survival, migration and invasion of lung cancer cells.	NSCLC	(77)
Datelliptium	RET transcription inhibitor, and suppression of EMT and thyroid carcinoma metastasis	Medullary thyroid carcinoma	(141)
LT-171-861	FLT3 inhibitor	Acute myeloid leukemia	(91)
miR-199b-5p	EMT inhibition	Prostate cancer	(59)
Foretinib	c-MET receptor inhibition	Glioblastoma, and Gastric Cancer	(142, 143)
Curcumin	Inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways	Different cancers	(4)
*NSCLC, Non-small cell lung cancer; HCC, Hepatocellular carcinoma; CRC, Colorectal cancer; RCC, Renal carcinoma; CSF1R, Colony-stimulating factor 1 receptor; ERBB2, Erb-b2 receptor tyrosine kinase 2; HER2, Human epidermal growth factor receptor 2; EGFR, Epidermal growth factor receptor; PDGF, Platelet-derived growth factor; VEGF, Vascular endothelial growth factor; EMT, Epithelial-to-mesenchymal transition; STAT3, signal transducer and activator of transcription 3; RET, Rearranged during transfection.

The non-coding RNA miR-199b-5p, acts as a cancer inhibitor in numerous human cancers, including prostate cancer metastasis. A recent report suggested the role of the miR-199b-5p-DDR1-ERK signaling axis in the treatment of prostate cancer through EMT inhibition (59).

It has been demonstrated that RTK signaling has a critical role in immunosuppression in cancer. The activation and overexpression of some RTKs, such as EGF receptor, c-Kit, ErbB2, ErbB3, and Met, each of which bind to Src homology and collagen A (ShcA), are involved in HER2/neu (human epidermal growth factor receptor 2) positive and basal-like breast cancer pathogenesis (60–62). ShcA binds to RTKs and can promote extracellular signaling which controls cellular proliferation, invasion, and angiogenesis, Indeed, increased ShcA signaling was associated with increased progression and recurrence in breast cancer patients (62, 63). Therefore combining immune-based therapies with RTK inhibitors could have promising therapeutic benefit in breast cancer.

On the other hand, other studies have shown that monotherapy approaches targeting RTKs may not be clinically effective, but combinations of RTKIs attacking several different RTKs has better potential for cancer treatment. For instance Crizotinib (a RTKI for c-Met) demonstrated an anticancer effect in breast cancer cells in combination with endocrine drugs through simultaneous downregulation of c-Met and estrogen receptors (64). In another study, it was shown that the combination of targeting both mTOR and c-Met signaling pathways could have better effects on epithelioid sarcoma tumors (65). In another study, Erlotinib plus Tivantinib was more effective than Erlotinib alone in NSCLC (66). Xu et al. showed that the combined inhibition of both EGFR and c-Met was successful in lung cancer treatment (67).

Some monoclonal antibodies acting as RTKs, such as trastuzumab and pertuzumab, bind to HER2 to prevent receptor dimerization. These TKIs are effective in both localized and metastatic forms of breast and gastric cancer that overexpress HER2, with improvement in the outcomes of breast cancer treatment (68). Mendes et al. reported that the combination of trastuzumab or pertuzumab with other chemotherapy drugs was accompanied by increased overall survival of HER2 + metastatic breast cancer patients, up to 56 months in comparison with chemotherapy alone with only 20 months survival time (69). Three main strategies for targeting the HER2 signaling pathway involved in breast cancer progression have been introduced, such as TKIs (lapatinib, tucatinib, and neratinib), monoclonal antibodies (pertuzumab and trastuzumab), and antibody-drug conjugates (DS-8201a and T-DM1) (70).

Fu. et al. studied a novel immunotherapeutic approach for CRC patient treatment. This study evaluated the effect of a combination therapy of the RTKI foretinib plus an anti-PD-1 antibody in CRC. They showed that this combination therapy suppressed tumor growth, prolonged overall survival, and improved anticancer immunity. T cell infiltration was increased, while tumor-associated macrophages (TAMs) and M2 phenotype TAMs were reduced, which eventually inhibited tumor development. Furthermore, JAK2-STAT1 pathway activation led to increased PD-L1 expression levels. So, the combination therapy of foretinib plus anti-PD-1 antibody could be a useful in CRC immunotherapy (71).

Other monoclonal antibodies against RTKs, such as panitumumab and cetuximab targeting EGFR/EGF are often used in metastatic CRC treatment. It was reported that after combining these antibodies with standard chemotherapy for early CRC, the overall survival of patients was prolonged by approximately 1.5 months (8.5 to 10 months). This benefit was only found in CRC patients with wild-type RAS because inhibition of RTK ligand binding to an active downstream protein kinase is ineffective (72, 73). In addition, Zhang et al. reported that cetuximab could improve the anticancer effect of AZD6244, a MAPK inhibitor, in CRC cells, and this co-inhibition could be a potential treatment option in CRC patients (74).

Ramucirumab is a monoclonal antibody targeting VEGF/VEGFR2 binding used in advanced or metastatic CRC, gastric, gastro-oesophageal, and NSCLS by inhibiting angiogenesis of tumors. Fuchs et al. reported that in the ramucirumab group of advanced or metastatic gastric and gastroesophageal cancer patients, the survival rate was 5.2 months, but in the placebo group it was 3.8 months, suggesting that VEGFR-2 signal inhibition using ramucirumab could be an important therapeutic option in advanced gastric cancer (75, 76).

Zheng et al. (2021) evaluated the antitumor therapeutic potential of W2014-S (a STAT3 inhibitor) in NSCLC. STAT3 is an important oncogenic factor leading to acquired resistance to targeted therapy. The results showed that W2014-S inhibited STAT3 dimerization and signaling in NSCLC cell lines, and redued proliferation, metastasis, and survival of cancer cells. In conclusion, W2014-S could be used in the treatment of NSCLC (77).

Lai et al. studied the therapeutic effect of DBPR114, a new FLT3/aurora kinase (AURK) multikinase inhibitor in advanced HCC. They demonstrated that the growth inhibition of HCC cells via DBPR114 was due to increased apoptosis, anti-angiogenic effects, cell cycle arrest, and the formation of polyploid and multinucleated cells. Moreover, the reduction of AURK phosphorylation levels by DBPR114 was also observed. As a result, they suggested that targeting FLT3/AURK could be a novel therapeutic approach in HCC patients (78).

Some TKIs, including erlotinib, gefitinib, afatinib (79, 80), osimertinib (81–83), and momelotinib (84) have been approved for metastatic lung adenocarcinoma treatment, leading to longer progression-free survival when combined with chemotherapy. Zhang et al. investigated the TKI almonertinib to inhibit proliferation and migration, and increase apoptosis in NSCLC cells (H1975 and PC-9). The main mechanism for this effect may be inhibition of the EMT and metalloproteinase expression (85). Osimertinib is the most effective TKI because of its longer progression-free survival compared to other similar drugs. It has been suggested that mutations in EGFR-encoding genes, most frequently an exon 19 deletion/exon 21 substitution, and also a mutation in exon 20, may be an important cause of lung adenocarcinoma and metastatic NSCLC (81, 86).

Expression of chimeric proteins through the fusion of NTRK genes with 5' partner genes could lead to NTRK fusion-driven cancers by ligand-independent kinase activation. Recently larotrectinib has been introduced as a therapeutic agent against solid tumors with NTRK fusion and Trk gene translocations (87). Moreover, lapatinib has been used in treatment of metastatic HER2 + breast cancer (69, 88), and bevacizumab has been tested in advanced NSCLC and breast cancer by inhibiting VEGF/VEGFR binding (89, 90). LT-171-861 is a new FLT3 inhibitor (91), and midostaurin has been tested in FLT3-mutated positive systemic mastocytosis and acute myeloid leukemia (92). Other targeted TKI therapies, include dabrafenib (93), vemurafenib (94) and trametinib (95) targeting RAF protein kinases, and inhibiting MEK in melanoma.

In one study, the immunotherapy effects of targeting of AXL RTK using enapotamab vedotin (EnaV), an antibody-drug conjugate, in immunotherapy-resistant cancer models, such as melanoma and lung cancer was assessed. The results showed the induction of inflammatory responses, activation of cytotoxic T cells, and tumor cell killing. The combination of EnaV with tumor-specific T cells increased the cure rate of treatment resistant melanoma and lung cancer (96). In general, combining RTKI drugs with other common chemotherapy drugs or radiotherapy can increase the therapeutic effectiveness compared to RTKI monotherapy. Combined therapy is superior in preventing tumor cell proliferation and inhibiting intracellular signaling cascades (Table 3) (97).

Table 3

**The summary of RTKIs and/or other RTKIs and chemotherapies combination studies to overcome drug resistance.**
RTKIs + Other RTKIs/chemotherapy agent	Cancer type	References
Osimertinib + Pemetrexed	NSCLC	(107)
R428 + Temozolomide	Glioblastoma	(112)
Sorafenib + DBPR114	HCC	(78)
BMX inhibitor (CHMFL-BMX-078) + Vemurafenib	Melanoma	(144)
W2014-S + Gefitinib + Erlotinib	NSCLC	(77)
Gefitinib + allogeneic CD8 + CD56 + NKT killer cells	NSCLC	(145)
Savolitinib + Gefitinib	NSCLC	(146)
Anlotinib + Gefitinib	NSCLC	(147)
Cabozantinib + Atezolizumab	Prostate cancer	(148)
AXL inhibitor + Cisplatin	Ovarian cancer	(149)
Camrelizumab + Famitinib	Platinum-resistant ROC	(113)
Lurasidone + Osimertinib	Not mentioned	(150)
Anlotinib + RFA	Lung squamous cell carcinoma	(151)
Selpercatinib + Crizotinib	Lung and thyroid cancers	(114)
Osimertinib + siROR1	Lung cancer	(152)
Avelumab + Axitinib	Advanced HCC	(153)
Foretinib + anti-PD-1 antibody	CRC	(71)
Pyrotinib + Carboplatin	Breast cancer	(154)
Vandetanib + Everolimus	Resistant advanced solid tumors	(109)
Foretinib + Entrectinib	CNS metastases	(155)
*NSCLC, Non-small cell lung cancer; HCC, Hepatocellular carcinoma; ROC, Recurrent ovarian cancer; CRC, Colorectal cancer; CNS, Central nervous system; RFA, Bronchoscope-guided radiofrequency ablation; siROR1, small interfering RNA (siRNA) targeting ROR1.

The main obstacle to the effective treatment of many cancers is the development of resistance to chemotherapy drugs by tumor cells. Different mechanisms are involved in this chemotherapy resistance, including the prevention of cell death and apoptosis, and increased EMT or DNA damage repair (32). Furthermore, despite the success of several targeted therapies in different cancers, leading to increased progression-free survival rates and complete responses in some cases, recurrence has been attributed to primary (intrinsic) or secondary (acquired) drug resistance (98). In primary resistance, the tumor does not respond to the targeted therapy despite displaying molecular changes that predispose the tumor to RTKI treatment. The patient with secondary resistance initially responds to treatment; but the cancer recurs and progresses with restoration of the growth and invasion of the tumor. The mechanisms of primary resistance are mostly unclear but may result from a small fraction of cells that have amplifications or mutations in the drug target, or have similar changes to those found in secondary resistance (18).

Drug resistance is accepted as a major obstacle in the treatment of cancer and cancer management (99), and the increasing incidence of drug-resistant tumors requires further research before cancer can be cured (99). Acquired drug resistance in cancer therapy can be caused by genetic or environmental alterations in related metabolic signaling pathways that select for resistant cells (100). In addition, it has been suggested that mutations in the target proteins which lead to a decrease in the binding between RTKs and drugs, or overexpression of cellular transport proteins resulting in decreased intracellular drug concentrations are other causes of this resistance (57). Hence, the identification of molecular drug targets is essential to reduce the survival of cancer cells or prevent the escape from the immune system. In this context, the dysregulated expression of RTKs may play a causal role in drug resistance and can be serve as an important target for drug development (39, 99). For example, drug resistance in chronic myelogenous leukemia after treatment with imatinib mesylate was caused by mutations in the RTK domain or the overexpression of Bcr-Abl, which is specific for drug binding (101).

In addition, acquired resistance to both irreversible and reversible EGFR-TKIs, including osimertinib and gefitinib, has been reported in NSCLC and lung adenocarcinoma due to EGFR-dependent and EGFR-independent mechanisms. These include mutations in the EGFR kinase domain duplication (EGFR-KDD) (102) or in the EGFR gene (103), mutations in KRAS exon 3 (R68S) (104), and the involvement of hsa_circ_0005576 via miR-512-5p/IGF1R signaling (105). Acquired drug resistance in EGFR-mutant NSCLC patients is a common reason for the limited long-term efficacy of targeted therapy (106). Takano. et al. evaluated the synergistic therapeutic effects of EGFR-TKI osimertinib plus pemetrexed (a chemotherapy drug commonly used in pleural mesothelioma and NSCLC) against PC-9 and H1975 NSCLC cell lines. The authors concluded that resistance to chemotherapy could be delayed by treatment with the osimertinib + pemetrexed combination. Since overexpression of the anti-apoptotic gene Polo-like kinase 1 (Plk1) may be a cause of acquired resistance to RTKIs, combination therapy reduced Plk1 expression in PC-9 and H1975 cells, resulting in more apoptosis and inhibition of proliferation in cancer cells (107). Furthermore, the overexpression of MUSASHI-2 (MSI2) (an RNA-binding protein) and Nanog (a stemness core protein) has been investigated as a new mechanism for resistance to EGFR-TKIs, including osimertinib or gefitinib (108). In agreement with this hypothesis, the knockdown of MSI2 and Nanog genes reinstated sensitivity to EGFR-TKIs in NSCLC cells in vivo and in vitro. Finally, combining EGFR-TKIs with an agent targeting the MSI2-Nanog axis could effectually inhibit acquired resistance (108).

The enhanced anticancer effects of vandetanib, a TKI targeting RET, VEGFR, and EGFR plus everolimus (a mTOR inhibitor) in refractory advanced solid cancers was reported in one preclinical study (109). This study assessed the maximum tolerated dose, safety, dose-limiting toxicity, and the recommended phase II dose of vandetanib + everolimus in patients. The combination of vandetanib + everolimus produced some side effects (e.g., rash, fatigue, mucositis, and diarrhea), but the mean progression-free survival and overall survival rates were 4.1 and 10.5 months, respectively, in 80 patients. Wang et al. also reported that knockdown of long non-coding RNA (lncRNA)-PCAT-1, an important factor in resistance to gefitinib in NSCLC cells, could improved the sensitivity to gefitinib, increase apoptosis, and inhibit GSK3 and AKT phosphorylation in H1299/GR cells. Thus this lncRNA could be a potential target for enhancing gefitinib efficacy (110). In another study by Satoh et al., combination therapy with erlotinib, bevacizumab plus osimertinib after acquired resistance emerged in NSCLC patients could be an option for these patients suffering from acquired resistance therapy to osimertinib alone (111). Moreover, in another study, it was reported that the combination of gefitinib plus W2014-S (a STAT3 inhibitor) could overcome acquired resistance of EGFR-TKIs (gefitinib and erlotinib) in NSCLC patients in order to improve the anticancer effects of gefitinib in EGFR-TKI resistant lung cancer patients (77).

In a study by Scherschinski et al.,, the synergistic effect of RTK-AXL plus temozolomide (TMZ) was assessed with regard to tumor progression and resistance to treatment in the glioblastoma multiforme (GBM) cell lines, U118MG and SF126. They showed that RTX-AXL overexpression results in therapy resistance, but combination therapy with TZM + TKI R428 (a selective small molecule Axl inhibitor) considerably increased the therapeutic effects. This study underlined the role of RTK-AXL in intrinsic and acquired therapy resistance (112). In other cancers such as recurrent ovarian cancer (ROC), combination therapy using an immune checkpoint inhibitor (e.g., camrelizumab) plus a RTKI (e.g., famitinib) in platinum-resistant ROC therapy was tested in a multicenter, open-label, phase 2 clinical trial. This study showed that this combination therapy could improve results in platinum-resistant ROC patients (113).

Intrinsic and acquired resistance to sorafenib in HCC patients could be overcome using a FLT3/AURK kinase inhibitor (DBPR114). DBPR114 remarkably delayed tumor growth after treatment, and lengthened survival time compared with the regorafenib group (78). The acquired resistance to selpercatinib, a RET kinase inhibitor approved for some cancers (lung and thyroid cancer) was studied by Rosen et al. (2021). They demonstrated that the elevated MET expression in RET fusion⁺-cancer cells could be a cause of resistance to RET-directed therapy in advanced NSCLC. They also suggested that this resistance could be overcome by a combination therapy with selpercatinib plus crizotinib (114). It has been shown that highly heterogeneous and phenotypically dynamic cancers should be treated with a combination of multiple drugs (including a chemotherapy drug plus an RTKI or multiple RTKIs) to overcome drug resistance.

Many studies have focused on mutated or overexpressed RTKs in almost all types of cancer, and have attempted to design and extend RTK inhibitors for improved treatment of the disease. Despite the complexity of the relationship between RTK oncogene activation and the onset of human cancer, several RTK oncogenes have been identified in various human cancers. Molecular targeted therapy has considerably improved the treatment outcome of various cancers, with fewer treatment-related adverse effects. Compared to conventional chemotherapy, targeted therapy offers a more patient-friendly treatment approach (115).

The use of a combination of low-dose multiple drugs may be preferable to single drugs, but this requires further investigation. Firstly, it is important to understand the signaling pathways involved in tumor progression and metastasis. Secondly, the combination drug targets must be identified, in order to achieve effectual suppression of complex networks. Thirdly, the dose of each drug should be as low as possible, and at the same time be non-toxic and effective in combination. Eventually, it must be determined whether the various drug combinations are effective, how many treatments are adequate, and in what order (116). Overall, in cancers with high heterogeneity and phenotypical traits, combination therapy using several drugs (including chemotherapy drugs with RTKIs or multiple RTKIs) are required for effective results in the treatment of cancer as well as to overcome drug resistance.

Despite many valuable clinical studies, more studies are required to better understand the molecular changes occurring downstream of unregulated RTKs, that may help diagnose, predict and treat different cancers to lower cancer mortality. In addition, these molecular changes may also act as appropriate therapeutic targets for specific drugs.

Declaration of competing interest

MRH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; Hologenix Inc. Santa Monica, CA; Vielight, Toronto, Canada; JOOVV Inc, Minneapolis-St. Paul MN; Sunlighten, Kansas City, MO; Consulting; USHIO Corp, Japan; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany; Klox Asia, Guangzhou, China. Stockholding: Niraxx Light Therapeutics, Inc, Irvine CA; JelikaLite Corp, New York NY. The other authors declare that they have no competing interests.

Acknowledgements

The authors would like to thank all of those whose fruitful research has contributed in any way to the elucidation of receptor tyrosine kinase role in cancer pathogenesis and receptor tyrosine kinase inhibitors in cancer therapy.

Author contributions

NE and EF designed the review paper and wrote the manuscript, HGh, SP, RKh, RV and HM contributed to writing, editing the manuscript and preparing the figures and tables; AA, MRH and ARA reviewed and revised the final version of manuscript and supervised the study.

Funding

MRH was supported by US NIH Grants R01AI050875 and R21AI121700. Other author(s) received no financial support for the research, authorship, and/or publication of this article.

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Receptor Tyrosine Kinase Inhibitors in Cancer Immunotherapy

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Abstract

Figures

Introduction

Rtk Structure, Activation Mechanisms, And Function

Ligand-induced homo- or heterodimerization of the receptor

Activation of the cytoplasmic kinase domains and tyrosine phosphorylation

Activation of multiple intracellular signaling cascades

The Roles Of Rtks In Cancer

Rtkis And Cancer Therapy

Intrinsic And Acquired Resistance To Rtkis In Different Cancers

Conclusion

Declarations

References

Status:

Journal Publication

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