2. Academic Validation
  3. BRAFV600 and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation

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

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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