2. Academic Validation
  3. Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

  • Nat Commun. 2021 Sep 10;12(1):5386. doi: 10.1038/s41467-021-25700-6.
Fabin Dang  # 1,  Li Nie  # 1 2,  Jin Zhou  # 3 4,  Kouhei Shimizu 1,  Chen Chu 5,  Zhong Wu 4 6,  Anne Fassl 5,  Shizhong Ke 7,  Yuangao Wang 8,  Jinfang Zhang 1,  Tao Zhang 1,  Zhenbo Tu 1,  Hiroyuki Inuzuka 1,  Piotr Sicinski 5,  Adam J Bass 9,  Wenyi Wei 10
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 2 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, China.
  • 3 Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 7 Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 8 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. adam_bass@dfci.harvard.edu.
  • 10 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. wwei2@bidmc.harvard.edu.
  • # Contributed equally.
PMID: 34508104 DOI: 10.1038/s41467-021-25700-6
Abstract

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

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