Data from Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer

Cristina Guarducci,Agostina Nardone,Douglas Russo,Zsuzsanna Nagy,Capucine Heraud,Albert Grinshpun,Qi Zhang,Allegra Freelander,Mathew Joseph Leventhal,Avery Feit,Gabriella Cohen Feit,Ariel Feiglin,Weihan Liu,Francisco Hermida-Prado,Nikolas Kesten,Wen Ma,Carmine De Angelis,Antonio Morlando,Madison O'Donnell,Sergey Naumenko,Shixia Huang,Quang-Dé Nguyen,Ying Huang,Luca Malorni,Johann S Bergholz,Jean J Zhao,Ernest Fraenkel,Elgene Lim,Rachel Schiff,Geoffrey I Shapiro,Rinath Jeselsohn

doi:10.1158/1078-0432.c.7209085.v1

Abstract

<div>AbstractPurpose:Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.Experimental Design:We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.Results:We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET 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. Finally, genome-wide CRISPR/Cas9 knockout 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+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.</div>

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