Abstract 487P
Background
Recent therapeutic strategies for KRAS-mutated cancers have attracted considerable attention. The RAF/MEK clamp avutometinib, which we found, is in clinical phase I-3 studies 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 non-small-cell lung cancer (NSCLC) cells. We further investigated the efficacy of combining avutometinib with inhibitors of the feedback signal. We identified a biomarker for the efficacy of combination therapy through an in vitro study and analysis using the TCGA dataset.
Results
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.
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
M. Horinaka.
Funding
The Public Promoting Association Asano Foundation for Studies on Medicine (Yoshimura, Japan).
Disclosure
T. Yamada: Financial Interests, Personal, Research Grant: Ono Pharmaceutical, Janssen, AstraZeneca, Takeda Pharmaceutical; Financial Interests, Personal, Speaker, Consultant, Advisor: Eli Lilly, Chugai-Roshe. K. Takayama: Financial Interests, Personal, Research Grant: Chugai Pharmaceutical Co. Ltd, Ono Pharmaceutical; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Chugai Pharmaceutical Co. Ltd., MSD-Merck, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo. T. Sakai: Financial Interests, Personal, Research Grant: Otsuka Pharmaceutical, Taiho Pharmaceutical, Oncolys BioPharma; Financial Interests, Personal, Licensing Fees or royalty for IP: JT Pharmaceutical. All other authors have declared no conflicts of interest.