Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer.
Br J Cancer
; 131(2): 361-371, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38822146
ABSTRACT
BACKGROUND:
Recent therapeutic strategies for KRAS-mutated cancers that inhibit the MAPK pathway have attracted considerable attention. The RAF/MEK clamp avutometinib (VS-6766/CH5126766/RO5126766/CKI27) is promising for patients with KRAS-mutated cancers. Although avutometinib monotherapy has shown clinical activity in patients with KRAS-mutated cancers, effective combination strategies will be important to develop.METHODS:
Using a phosphorylation kinase array kit, we explored the feedback mechanism of avutometinib in KRAS-mutated NSCLC cells, and investigated the efficacy of combining avutometinib with inhibitors of the feedback signal using in vitro and in vivo experiments. Moreover, we searched for a biomarker for the efficacy of combination therapy through an in vitro study and analysis using the The Cancer Genome Atlas Programme dataset.RESULTS:
Focal adhesion kinase (FAK) phosphorylation/activation was increased after avutometinib treatment and synergy between avutometinib and FAK inhibitor, defactinib, was observed in KRAS-mutated NSCLC cells with an epithelial rather than mesenchymal phenotype. Combination therapy with avutometinib and defactinib induced apoptosis with upregulation of Bim in cancer cells with an epithelial phenotype in an in vitro and in vivo study.CONCLUSIONS:
These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the efficacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antineoplastic Combined Chemotherapy Protocols
/
Proto-Oncogene Proteins p21(ras)
/
Carcinoma, Non-Small-Cell Lung
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Epithelial-Mesenchymal Transition
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Lung Neoplasms
/
Mutation
Limits:
Animals
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Female
/
Humans
Language:
En
Journal:
Br J Cancer
Year:
2024
Document type:
Article
Affiliation country:
Japan
Country of publication:
United kingdom