Selective CDK7 inhibition suppresses cell cycle progression and MYC signaling while enhancing apoptosis in therapy-resistant estrogen receptor positive breast cancer

  • Clin Cancer Res. 2024 Feb 21. doi: 10.1158/1078-0432.CCR-23-2975.
Cristina Guarducci  1 ,  Agostina Nardone  2 ,  Douglas Russo  3 ,  Zsuzsanna Nagy  4 ,  Capucine Heraud  3 ,  Albert Grinshpun  1 ,  Qi Zhang  2 ,  Allegra Freelander  5 ,  Matthew Joseph Leventhal  6 ,  Avery Feit  7 ,  Gabriella Cohen Feit  2 ,  Ariel Feiglin  8 ,  Weihan Liu  9 ,  Francisco Hermida-Prado  3 ,  Nikolas Kesten  3 ,  Wen Ma  2 ,  Carmine De Angelis  10 ,  Antonio Morlando  11 ,  Madison O'Donnell  9 ,  Sergey Naumenko  12 ,  Shixia Huang  10 ,  Quang-De Nguyen  3 ,  Ying Huang  9 ,  Luca Malorni  13 ,  Johann S Bergholz Villafane  9 ,  Jean J Zhao  3 ,  Ernest Fraenkel  14 ,  Elgene Lim  15 ,  Rachel Schiff  10 ,  Geoffrey I Shapiro  3 ,  Rinath Jeselsohn  3
Affiliations
  • 1. Dana-Farber Cancer Institute, Boston, United States.
  • 2. Dana-Farber Cancer Institute, Boston, Ma, United States.
  • 3. Dana-Farber Cancer Institute, Boston, MA, United States.
  • 4. Dana-Farber/Harvard Cancer Center, Boston, MA, United States.
  • 5. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
  • 6. Massachusetts Institute of Technology, United States.
  • 7. Albert Einstein College of Medicine, Bronx, NY, United States.
  • 8. Harvard Medical School, Boston, MA, United States.
  • 9. Dana-Farber Cancer Institute, United States.
  • 10. Baylor College of Medicine, Houston, TX, United States.
  • 11. Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy.
  • 12. Harvard School of Public Health, Boston, MA, United States.
  • 13. Hospital of Prato, Prato, Italy.
  • 14. Massachusetts Institute of Technology, Cambridge, MA, United States.
  • 15. Garvan Institute, Darlinghurst, NSW, Australia.
PMID: 38381406 DOI: 10.1158/1078-0432.CCR-23-2975
Abstract

Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in Estrogen receptor (ER) positive (ER+) breast Cancer (BC). Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine resistant ER+ BC models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ BC. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ BC remain elusive. Herein, we sought to unravel these mechanisms.

Experimental design: We conducted multi-omic analyses in ER+ BC models in vitro and in vivo including models with different genetic backgrounds. We also performed genome wide CRISPR knock-out library screens to identify potential therapeutic vulnerabilities in CDK4/6i resistance models.

Results: We found that the on-target anti-tumor effects of CDK7 inhibition in ER+ BC are in part p53 dependent, involve cell-cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ETs and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118, however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Lastly, genome wide CRISPR/Cas9 screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i resistant models.

Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ BC. In addition, our study highlights the potential of increased MYC activity and intact P53 as predictors for sensitivity to CDK7 inhibitor-based treatments.

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