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

• DOI: 10.1158/1078-0432.c.7209085
• Publication Date: 2024-05-01T13:03:08Z
• Authors: Cristina Guarducci; Agostina Nardone; Douglas Russo; Zsuzsanna Nagy; Capucine Heraud; Albert Grinshpun; Qi Zhang; Allegra Freelander; Mathew Joseph Lev...; Avery Feit; Gabriella Cohen Feit; Ariel Feiglin; Weihan Liu; Francisco Hermida...; 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
• Keywords: Cyclin-dependent kinase 7

<div>AbstractPurpose:<p>Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER<sup>+</sup>) breast cancer. Cyclin-dependent kinase 7 (CDK7) candidate target endocrine-resistant ER<sup>+</sup> cancer models selective CDK7 (CDK7i) are development for the treatment of Nonetheless, precise mechanisms responsible activity CDK7i remain elusive. Herein, we sought unravel these mechanisms.</p>Experimental Design:<p>We conducted multi-omic analyses <i>in vitro</i> vivo</i>, including with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens identify potential therapeutic vulnerabilities CDK4/6i-resistant models.</p>Results:<p>We found that on-target antitumor effects inhibition part p53 dependent, involve cell cycle suppression c-Myc. Moreover, exhibited cytotoxic effects, distinctive from cytostatic nature ET CDK4/6i. resulted ER phosphorylation at S118; however, long-term increased signaling, supporting combination CDK7i. Finally, identified MYC signaling as putative CDK4/6i resistance, effectively inhibited models.</p>Conclusions:<p>Taken together, findings support investigation combined overcome resistance In addition, our study highlights c-Myc intact predictors sensitivity CDK7i-based treatments.</p></div>