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

The clinical development of farnesyltransferase inhibitors (FTI) for HRAS -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to HRAS -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 HRAS - vs KRAS - and NRAS -mutant cancers. HRAS -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to KRAS - and NRAS -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS -mutant lineages. To study the effect of comutations on FTI sensitivity, Hras ^G13R was transfected into 'RASless' ( Kras ^lox/lox ; Hras ^-/- ; Nras ^-/- ) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion or Pik3ca ^H1047R or Braf ^G466E transduction led to relative resistance to tipifarnib in Hras ^G13R MEFs in the presence or absence of Kras ^WT . Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. HRAS -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 HRAS -mutant tumors.
Competing Interests: Competing Interest Statement: No additional competing interests to disclose