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Research Article
Androgen receptor activity promotes resistance to BRAF-targeted melanoma therapy
Jennifer Wargo
MD Anderson
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3438-7576
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Treatment with molecularly-targeted therapy has revolutionized cancer care, including BRAF/MEK-targeted melanoma therapy. However responses are heterogenous and frequently not long-lasting. Novel strategies to target resistance are needed. We studied a cohort of patients with resectable metastatic melanoma treated with neoadjuvant BRAF/MEK-targeted therapy (n=52) and noted a strong sexual dimorphism in response to treatment, with female patients demonstrating significantly higher rates of a major pathologic response (MPR) (p=0.0001). RNA sequencing of tumors demonstrated enrichment of androgen-related genes in those failing to achieve MPR. Pre-clinical studies validated these findings, with significantly increased tumor growth in male vs female mice treated with BRAF/MEK inhibitors (BRAF/MEKi) (p=0.0005). Androgen receptor (AR) expression was upregulated in tumors of BRAF/MEKi-treated mice, and modulation of AR signaling via AR-blockade or castration was associated with significantly slower tumor growth (p=0.0001 and p=0.00004, respectively). Together, these results have important implications in the context of treatment with BRAF/MEKi-targeted therapy.
Keywords
cancer, targeted therapy, androgen, BRAF
Figure 1
Figure 2
Figure 3
This is a list of supplementary files associated with this preprint. Click to download.
- Suppfig1.pdf
Strong sexual dimorphism noted in response to neoadjuvant BRAF-MEK inhibition therapy in melanoma patients. A) Major pathologic response with ≤ 10% viable tumor in females and males. B) Enriched pathways in pre-treatment specimens between responders and non-responders.
- supplement2.pdf
Murine model of melanoma validates a sexual dimorphic response and suggests AR activity as a mechanism of resistance. A) Schematic demonstrating the experimental design for evaluating gender difference in response to DT treatment in immune competent and immunocompromised melanoma mouse models. B-C) Percent change in tumor volume for male and female C57Bl/6 mice implanted subcutaneously with BP cells that were treated with Vehicle or DT. n = 10 mice per group. Results from the second and third repeats of this experiment are shown in B and C, respectively.
- supplement3.pdf
Modulation of AR activity is associated with differential response to DT. A) Schematic demonstrating the experimental design for evaluating the effect of exogenous testosterone on response to DT treatment in female immune competent and immunocompromised melanoma mouse models. B) Schematic demonstrating the experimental design for evaluating the effect of AR blockade with Enzalutamide or castration on response to DT treatment in male immune competent and immune-compromised melanoma mouse models. C) Tumor volume in immune-compromised female mice treated with vehicle, DT, testosterone, or DT in combination with testosterone. D) Tumor volume in immune competent male mice treated with vehicle, DT, Enzalutamide, or DT in combination with Enzalutamide. E) Tumor volume in immune-compromised male mice treated with vehicle, castration, Enzalutamide, DT, or DT in combination with Enzalutamide or castration. For C-E, p-values were calculated for the final time point using two-sided Student’s t-test. F) Quantification of the percent of AR+ nuclei by immunofluorescence in BP tumors from male and female mice treated with vehicle, DT, testosterone or DT in combination with testosterone in females and Enzalutamide or DT in combination with Enzalutamide in males. P values were calculated using two-sided Student’s t-test. G) Immunofluorescence images of AR+ nuclei in BP tumors from male and female AR KO mice.
- SupplementalTable1.xlsx
Supplementary Table 1
- SupplementalTable2.xlsx
Supplementary Table 2
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Research Article
Androgen receptor activity promotes resistance to BRAF-targeted melanoma therapy
Jennifer Wargo
MD Anderson
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3438-7576
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 17 Aug, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Treatment with molecularly-targeted therapy has revolutionized cancer care, including BRAF/MEK-targeted melanoma therapy. However responses are heterogenous and frequently not long-lasting. Novel strategies to target resistance are needed. We studied a cohort of patients with resectable metastatic melanoma treated with neoadjuvant BRAF/MEK-targeted therapy (n=52) and noted a strong sexual dimorphism in response to treatment, with female patients demonstrating significantly higher rates of a major pathologic response (MPR) (p=0.0001). RNA sequencing of tumors demonstrated enrichment of androgen-related genes in those failing to achieve MPR. Pre-clinical studies validated these findings, with significantly increased tumor growth in male vs female mice treated with BRAF/MEK inhibitors (BRAF/MEKi) (p=0.0005). Androgen receptor (AR) expression was upregulated in tumors of BRAF/MEKi-treated mice, and modulation of AR signaling via AR-blockade or castration was associated with significantly slower tumor growth (p=0.0001 and p=0.00004, respectively). Together, these results have important implications in the context of treatment with BRAF/MEKi-targeted therapy.
Figure 1
Figure 2
Figure 3