Eur J Cancer. 2021 Apr 14;149:184-192. doi: 10.1016/j.ejca.2021.01.055. Online ahead of print.
ABSTRACT
BACKGROUND: RAS variant-related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established.
PATIENTS AND METHODS: Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations.
RESULTS: Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003).
CONCLUSIONS: These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.
PMID:33865203 | DOI:10.1016/j.ejca.2021.01.055
