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

ABSTRACT: 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.

SUBMITTER: Nigam A

PROVIDER: S-EPMC10371077 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Nigam Aradhya A Krishnamoorthy Gnana G Chatila Walid W Berman Katherine K Saqcena Mahesh M Walch Henry H Ho Alan A Schultz Nikolaus N Fagin James J Untch Brian B

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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 ca ...[more]

PMID: 37503077

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Project description:The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy.SignificanceThe complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.

Dataset Information

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

Publications

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

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