Chemotherapy failure is a devastating problem that frequently results from cancer multidrug resistance (MDR). MDR is often due to overexpression of proteins called ABC transporters, which can pump chemotherapy drugs out of cancer cells. However, there are currently no effective treatments for MDR. A new study tested whether adagrasib (MRTX849), a promising anticancer drug targeting a mutant KRAS protein, can help fight MDR in cancer cell lines overexpressing the ABC transporter ABCB1 and in mice with ABCB1-overexpressing tumors. Both in vitro and in vivo, adagrasib increased the anticancer efficacy of conventional chemotherapy drugs. Adagrasib did not change the expression level or location of ABCB1 in the cells to exert its MDR- reversing effects. Rather, it suppressed the ability of ABCB1 to pump the drugs out of the cancer cells, likely by preventing binding of the energy molecule ATP, which normally powers the transporter’s pumping action. In this way, adagrasib enabled the chemotherapy drugs to accumulate within the cancer cells and exert their intended effects. Although more clinical studies are needed, the findings identify adagrasib as a promising new MDR-reversing drug, providing hope for patients with hard-to-treat cancers.