Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors Journal Article

  

Authors:	Nigam, A.; Krishnamoorthy, G. P.; Chatila, W. K.; Berman, K.; Saqcena, M.; Walch, H.; Venkatramani, M.; Ho, A. L.; Schultz, N.; Fagin, J. A.; Untch, B. R.
Article Title:	Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors
Abstract:	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. © The Author(s), under exclusive licence to Springer Nature Limited 2024.
Keywords:	signal transduction; mitogen activated protein kinase; controlled study; gene mutation; genetics; mutation; neoplasm; neoplasms; mouse; animal; animals; mice; cell viability; embryo; prevalence; drug effect; drug resistance; pathology; drug resistance, neoplasm; enzyme inhibitor; cell line, tumor; genetic transfection; enzyme inhibitors; tumor cell line; western blotting; protein farnesyltransferase inhibitor; tipifarnib; fibroblast; genomics; drug therapy; k ras protein; protein p21; proto-oncogene proteins p21(ras); b raf kinase; procedures; farnesyltranstransferase; pi3k/akt signaling; quinolone derivative; quinolones; humans; human; article; farnesyl trans transferase; hras protein, human; malignant neoplasm; gene knockout
Journal Title:	Oncogene
Volume:	43
Issue:	37
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2024-09-06
Start Page:	2806
End Page:	2819
Language:	English
DOI:	10.1038/s41388-024-03095-0
PUBMED:	39152269
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85201421298&doi=10.1038%2fs41388-024-03095-0&partnerID=40&md5=daf02785e3cc8ecd06b7edaa55ddb1f2
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Brian Untch -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/219323