TY - JOUR
T1 - Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor- positive Breast Cancer
AU - Guarducci, Cristina
AU - Nardone, Agostina
AU - Russo, Douglas
AU - Nagy, Zsuzsanna
AU - Heraud, Capucine
AU - Grinshpun, Albert
AU - Zhang, Qi
AU - Freelander, Allegra
AU - Leventhal, Mathew Joseph
AU - Feit, Avery
AU - Feit, Gabriella Cohen
AU - Feiglin, Ariel
AU - Liu, Weihan
AU - Hermida-Prado, Francisco
AU - Kesten, Nikolas
AU - Ma, Wen
AU - De Angelis, Carmine
AU - Morlando, Antonio
AU - O'Donnell, Madison
AU - Naumenko, Sergey
AU - Huang, Shixia
AU - Nguyen, Quang Dé
AU - Huang, Ying
AU - Malorni, Luca
AU - Bergholz, Johann S.
AU - Zhao, Jean J.
AU - Fraenkel, Ernest
AU - Lim, Elgene
AU - Schiff, Rachel
AU - Shapiro, Geoffrey I.
AU - Jeselsohn, Rinath
N1 - Publisher Copyright:
© 2024 The Authors.
PY - 2024/5/1
Y1 - 2024/5/1
N2 - Purpose: 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 selectiveCDK7inhibitors (CDK7i) are in clinical development for the treatment of ER breast cancer. Nonetheless, the precisemechanisms 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 genomewide 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.
AB - Purpose: 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 selectiveCDK7inhibitors (CDK7i) are in clinical development for the treatment of ER breast cancer. Nonetheless, the precisemechanisms 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 genomewide 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.
UR - http://www.scopus.com/inward/record.url?scp=85192028076&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-2975
DO - 10.1158/1078-0432.CCR-23-2975
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 38381406
AN - SCOPUS:85192028076
SN - 1078-0432
VL - 30
SP - 1889
EP - 1905
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -