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

To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, a...

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Published in:Clinical cancer research 2023-06, Vol.29 (11), p.2144-2157
Main Authors: Rossi, Ferdinand, Liu, Mengyuan, Tieniber, Andrew, Etherington, Mark S, Hanna, Andrew, Vitiello, Gerardo A, Param, Nesteene J, Do, Kevin, Wang, Laura, Antonescu, Cristina R, Zeng, Shan, Zhang, Jennifer Q, DeMatteo, Ronald P
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Gastrointestinal Stromal Tumors - drug therapy
Gastrointestinal Stromal Tumors - genetics
Gastrointestinal Stromal Tumors - pathology
Humans
Imatinib Mesylate - pharmacology
Imatinib Mesylate - therapeutic use
Mutation
Myosins - genetics
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Proto-Oncogene Proteins c-kit - genetics
Receptor, Platelet-Derived Growth Factor alpha
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Summary:To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. 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. The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-22-0533