BRAFV600 and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation

  • bioRxiv. 2024 Dec 20:2024.12.19.629301. doi: 10.1101/2024.12.19.629301.
C Ryland Ill  1  2 ,  Nasreen C Marikar  1  2 ,  Vu Nguyen  3 ,  Varuna Nangia  1  2  4 ,  Alicia M Darnell  5  6 ,  Matthew G Vander Heiden  5  7 ,  Philip Reigan  3 ,  Sabrina L Spencer  1  2
Affiliations
  • 1. Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA.
  • 2. BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA.
  • 3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz, Aurora, CO, USA.
  • 4. University of Colorado School of Medicine, University of Colorado Anschutz, Aurora, CO, USA.
  • 5. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, MA, USA.
  • 6. Current address: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, NC, USA.
  • 7. Dana-Farber Cancer Institute, MA, USA.
PMID: 39763857 DOI: 10.1101/2024.12.19.629301
Abstract

Targeted kinase inhibitors are well known for their promiscuity and off-target effects. Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4. Blocking this off-target effect by co-drugging with a GCN2 inhibitor in A375 melanoma cells causes enhancement rather than suppression of Cancer cell outgrowth, suggesting that the off-target activation of GCN2 is detrimental to these cells. This result is mirrored in PC9 lung Cancer cells treated with erlotinib, an EGFR Inhibitor, that shares the same off-target activation of GCN2. Using an in silico kinase inhibitor screen, we identified dozens of FDA-approved drugs that appear to share this off-target activation of GCN2 and ATF4. Thus, GCN2 activation may modulate the therapeutic efficacy of some kinase inhibitors, depending on the Cancer context.

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