Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The RAS/MAPK pathway is a key target in cancer therapy, typically driven by single oncogene mutations.
• Hypermutant tumors, characterized by numerous somatic mutations, can complicate the identification of actionable genomic alterations.
• Replication repair-deficient (RRD) cancers are hypermutant and often affect children with genetic predispositions.

Purpose of the Study:

• To investigate the role of RAS/MAPK pathway mutations in RRD cancers.
• To determine if RRD hypermutant tumors are sensitive to targeted therapies like MEK inhibition.

Main Methods:

• Analysis of RAS/MAPK mutation enrichment in RRD cancers.
• Assessment of RAS/MAPK pathway activation at transcriptional and protein levels in patient-derived RRD tumors.
• Evaluation of MEK inhibitor efficacy in vitro and in vivo models, and in patient treatment.

Main Results:

• RRD cancers exhibit significant enrichment of RAS/MAPK pathway mutations (P = 10^-8).
• These mutations are subclonal, increase in frequency over time, and lead to pathway activation.
• MEK inhibition demonstrated efficacy in vitro, in vivo, and resulted in durable responses in patients with RRD hypermutant gliomas.

Conclusions:

• Hypermutant RRD cancers are addicted to the RAS/MAPK pathway, making them susceptible to targeted therapies.
• Targeting the activated RAS/MAPK pathway offers a promising therapeutic strategy for polyclonal hypermutant cancers.
• This study highlights the potential of pathway-targeted therapy in RRD hypermutant tumors.