Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor.

ABSTRACT:

Purpose

To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy.

Experimental design

We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression.

Results

The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskelet

SUBMITTER: Rossi F 

PROVIDER: S-EPMC10239357 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature