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

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

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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