1. Academic Validation
  2. Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer

Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer

  • Clin Cancer Res. 2021 Apr 1;27(7):1855-1863. doi: 10.1158/1078-0432.CCR-20-3871.
Giulia Petroni 1 Aitziber Buqué 1 Takahiro Yamazaki 1 Norma Bloy 1 Maurizio Di Liberto 2 Selina Chen-Kiang 2 3 4 Silvia C Formenti 1 4 5 Lorenzo Galluzzi 6 4 7
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Weill Cornell Medical College, New York, New York.
  • 2 Department of Pathology, Weill Cornell Medical College, New York, New York.
  • 3 Graduate Program of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, New York.
  • 4 Sandra and Edward Meyer Cancer Center, New York, New York.
  • 5 Department of Medicine, Weill Cornell Medical College, New York, New York.
  • 6 Department of Radiation Oncology, Weill Cornell Medical College, New York, New York. deadoc80@gmail.com.
  • 7 Caryl and Israel Englander Institute for Precision Medicine, New York, New York.
Abstract

Purpose: Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor-positive (ER+) breast Cancer to radiotherapy. However, these findings were obtained in human ER+ breast Cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.

Experimental design: We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER+ and ER-negative (ER-) breast Cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast Cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival in vitro, as well as tumor growth, overall survival, and metastatic dissemination in vivo.

Results: Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects in vitro, correlating with suboptimal tumor control in vivo. However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested in vitro with enhanced cytostasis and loss of clonogenic potential, as well as in vivo with improved local and systemic tumor control.

Conclusions: Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast Cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6抑制剂
    CDK