Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers.

ABSTRACT:

Background

Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor.

Materials and methods

Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then

SUBMITTER: Rustgi N 

PROVIDER: S-EPMC10769795 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature