SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2990-3000
Number of pages11
JournalCancer Research
Volume77
Issue number11
DOIs
Publication statusPublished - Jun 1 2017
Externally publishedYes

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Focal Adhesion Protein-Tyrosine Kinases
src-Family Kinases
Lung Neoplasms
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Therapeutics
osimertinib
Clinical Trials
Apoptosis
Mutation
Inhibition (Psychology)
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer. / Ichihara, Eiki; Westover, David; Meador, Catherine B.; Yan, Yingjun; Bauer, Joshua A.; Lu, Pengcheng; Ye, Fei; Kulick, Amanda; De Stanchina, Elisa; McEwen, Robert; Ladanyi, Marc; Cross, Darren; Pao, William; Lovly, Christine M.

In: Cancer Research, Vol. 77, No. 11, 01.06.2017, p. 2990-3000.

Research output: Contribution to journalArticle

Ichihara, E, Westover, D, Meador, CB, Yan, Y, Bauer, JA, Lu, P, Ye, F, Kulick, A, De Stanchina, E, McEwen, R, Ladanyi, M, Cross, D, Pao, W & Lovly, CM 2017, 'SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer', Cancer Research, vol. 77, no. 11, pp. 2990-3000. https://doi.org/10.1158/0008-5472.CAN-16-2300
Ichihara, Eiki ; Westover, David ; Meador, Catherine B. ; Yan, Yingjun ; Bauer, Joshua A. ; Lu, Pengcheng ; Ye, Fei ; Kulick, Amanda ; De Stanchina, Elisa ; McEwen, Robert ; Ladanyi, Marc ; Cross, Darren ; Pao, William ; Lovly, Christine M. / SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer. In: Cancer Research. 2017 ; Vol. 77, No. 11. pp. 2990-3000.
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AU - Cross, Darren

AU - Pao, William

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