Blog
About

4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer.

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Journal
          Cancer Res.
          Cancer research
          American Association for Cancer Research (AACR)
          1538-7445
          0008-5472
          Jun 01 2017
          : 77
          : 11
          Affiliations
          [1 ] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [2 ] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [3 ] Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [4 ] Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [5 ] Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [6 ] Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
          [7 ] Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
          [8 ] AstraZeneca Oncology, Cambridge, United Kingdom.
          [9 ] Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
          [10 ] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. christine.lovly@vanderbilt.edu.
          Article
          0008-5472.CAN-16-2300 NIHMS867387
          10.1158/0008-5472.CAN-16-2300
          5467531
          28416483

          Comments

          Comment on this article