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Ref Type Journal Article
PMID (39152269)
Authors Nigam A, Krishnamoorthy GP, Chatila WK, Berman K, Saqcena M, Walch H, Venkatramani M, Ho AL, Schultz N, Fagin JA, Untch BR
Title Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Oncogene 43 37 2024 Sep 2806-2819 Oncogene
URL
Abstract Text In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

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