SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition

Direct targeting of the KRAS-G12C–mutant protein using covalent inhibitors (G12Ci) acts on human non–small cell lung cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the KRAS-G12C mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma. A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance. Functional studies demonstrated that the transcription factor JUN drives ABCC1 expression, resulting in multidrug resistance. An unbiased drug screen identified the tyrosine kinase inhibitor dasatinib that potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation, avoiding multidrug resistance and tumor suppression in vitro as well as in suitable preclinical mouse models and patient-derived organoids. SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.