Cooperative Genomic Lesions in HRAS-Mutant Cancers Predict Resistance to Farnesyltransferase Inhibitors.

The clinical development of farnesyltransferase inhibitors (FTI) for -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to -mutant tumors and study their effect on FTI sensitivity. Using targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases we identified co-mutations in - vs - and -mutant cancers. -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to - and -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 mutations were more prevalent in -mutant lineages. To study the effect of comutations on FTI sensitivity, was transfected into 'RASless' (;;) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of or deletion or or transduction led to relative resistance to tipifarnib in MEFs in the presence or absence of Kras. Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. -mutant tumors demonstrate lineage demonstrate lineage-dependent MAPK/PI3K pathway alterations that confer relative resistance to tipifarnib. Combined FTI and MEK inhibition is a promising combination for -mutant tumors.