In this study, we used next-generation sequencing technologies coupled with genome-wide CRISPR analysis to demonstrate that MRTX849 induces multidrug resistance in human NSCLC and PDAC cells by selectively up-regulating the expression of adenosine triphosphate (ATP) binding cassette subfamily C member 1 (ABCC1) transporter. Here, ABCC1 is linked to non-small cell lung carcinoma.