journal contribution
posted on 2023-03-31, 00:28 authored by Eiki Ichihara, David Westover, Catherine B. Meador, Yingjun Yan, Joshua A. Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa de Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M. Lovly (1) Figure S1. Sustained AKT and MAPK pathway signaling following EGFR TKI treatment in EGFR-mutant lung cancer cells. (2) Figure S2. Analysis of cells treated with TKIs after 96 hours. (3) Figure S3. HER3 reactivation after osimertinib treatment. (4) Figure S4. Combination osimertinib plus SFK inhibitor decreases SFK signaling and results in better cell growth inhibition. (5) Figure S5. Upregulation of SFKs and FAK upon EGFR inhibition in EGFR-mutant lung cancer cells. (6) Figure S6. Osimertinib compared to osimertinib plus dasatinib in an osimertinib-sensitive xenograft model. (7) Figure S7. Extracellular interactions may influence osimertinib potency. (8) Figure S8. SFK/FAK pathway inhibition most potently enhances the effects of osimertinib. (9) Figure S9. Analysis of osimertinib (AZD9291) resistant lung cancer cell lines.
Funding
NIH
National Cancer Institute
Uehara Memorial Foundation
T32 training grant
V Foundation Scholar-in-Training Award
AACR-Genentech Career Development Award
Damon Runyon Clinical Investigator Award
LUNGevity Career Development Award
History
ARTICLE ABSTRACT
Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990–3000. ©2017 AACR.
