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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Farnesyltransferase inhibitors (FTI) have shown mixed clinical responses in HRAS-mutant tumors.
• Co-occurring genetic mutations are suspected to influence FTI sensitivity.
• Understanding these cooperative genetic events is crucial for optimizing HRAS-mutant cancer treatment.

Approach:

• Analyzed targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases to identify co-mutations in HRAS-mutant versus KRAS- and NRAS-mutant cancers.
• Utilized genetically engineered mouse embryonic fibroblasts (MEFs) to model HRAS mutations and assess FTI sensitivity.
• Investigated the impact of specific co-mutations (BRAF, NF1, PTEN, PIK3CA) on FTI response.
• Evaluated the efficacy of combined FTI and MEK inhibition therapy.

Key Points:

• HRAS-mutant cancers exhibit a higher frequency of co-altered mutations in MAPK, PI3K, or RTK pathway genes compared to KRAS- and NRAS-mutant cancers.
• Specific mutations, including Class 3 BRAF, NF1, PTEN, and PIK3CA, were more prevalent in HRAS-mutant lineages.
• Co-mutations in PTEN, NF1, PIK3CA, or BRAF conferred relative resistance to FTI (tipifarnib) in HRAS-mutant models.
• Combined FTI and MEK inhibition demonstrated efficacy, sensitizing cells to FTI treatment, even in the presence of PI3K pathway co-mutations.

Conclusions:

• HRAS-mutant tumors display lineage-dependent alterations in the MAPK/PI3K pathways, contributing to relative FTI resistance.
• Combined FTI and MEK inhibition represents a promising therapeutic strategy for HRAS-mutant tumors.
• Further research into specific co-mutation profiles can guide personalized treatment approaches.