Cancer is a genetic disease that develops from various genomic alterations leading to uncontrolled cell proliferation. Recent advances in genomic technologies have revolutionized the development of novel anti-cancer drugs targeting specific oncogenic pathways, however, drug response varies among individuals due to differences in genetic makeup. Therefore, identifying genomic biomarkers reliably predicting drug sensitivity and resistance is crucial for optimal cancer treatment. Here, I present novel genetic factors predicting FGFR inhibitor sensitivity and mTOR inhibitor resistance. Comprehensive genomic and pharmacogenomic profiling of pre-clinical and clinical tumor samples revealed the clinical actionability of C-terminal truncated FGFR2, a prevalent genomic event typically generated through in-frame or non-canonical genomic rearrangements. We suggest that cancers containing any FGFR2 variants with a truncated exon 18 should be considered for FGFR-targeted therapies. To identify resistance factors against mTOR blockade, multi-omics analysis for breast cancer murine models was performed, which revealed recurrent activation of MYC in tumors that acquired resistance to mTOR blockade. MYC counteracts mTOR inhibition effects by partially restoring protein translation. MYC status was significantly associated with poor response to everolimus therapy in ER-positive tumors, suggesting that MYC is a clinically relevant driver of mTOR inhibitor resistance.