Faculty Collaboration Database

Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors. Eur J Cancer 2021 May;149:184-192

Date

04/18/2021

Pubmed ID

33865203

DOI

10.1016/j.ejca.2021.01.055

Scopus ID

2-s2.0-85104075728 (requires institutional sign-in at Scopus site)   3 Citations

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.

Author List

Kato S, Porter R, Okamura R, Lee S, Zelichov O, Tarcic G, Vidne M, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Agents
Female
Genes, ras
Genetic Predisposition to Disease
Humans
MAP Kinase Kinase Kinases
Male
Middle Aged
Mitogen-Activated Protein Kinases
Mutation
Neoplasms
Phenotype
Protein Kinase Inhibitors
Signal Transduction
Time Factors