MET-Pyk2 Axis Mediates Acquired Resistance to FGFR Inhibition in Cancer Cells

• DOI: 10.3389/fonc.2021.633410
• Publication Date: 2021-04-07T15:19:04Z
• Authors: Kamila Kitowska; Monika Gorska-Arcisz; Dima Antoun; Izabela Zarczynska; Dominika Czaplinska; Adrian Szczepaniak; Andrzej C. Sklada...; Maciej Wieczorek; Aleksandra Stanczak; Monika Skupinska; Rafal Sadej
• Keywords: Pyk2; 03 medical and health sciences; 0302 clinical medicine; Oncology; FGFR; acquired resistance; MET; cancer; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282; 3. Good health

Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression wide range human cancers. Clinical data demonstrating the dependence cancer cells on FGFRs signaling clearly indicate these molecular targets anti-cancer therapies. Despite increasing number tyrosine kinase inhibitors (TKIs) being investigated clinical trials, acquired resistance to drugs poses serious therapeutic problem. In this study, we focused novel pan-FGFR inhibitor—CPL304110, currently phase I trials adults with advanced solid malignancies. We analyzed sensitivity 17 cell lines derived from cancers aberrant i.e. non-small lung cancer, gastric bladder CPL304110. order explore mechanism inhibitor, developed sensitive their variants resistant Herein, for first time revealed that process inhibitor was associated increased expression MET lung, gastric, cells. Overexpression NCI-H1703, SNU-16, RT-112 well treatment HGF resulted impaired response inhibition activity. Moreover, demonstrated overexpressing displayed enhanced migratory abilities what accompanied levels Pyk2 expression. Importantly, activity restored Our results demonstrate HGF/MET-Pyk2 axis confers common study suggests targeting MET/Pyk2 could be an approach overcome inhibition.