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

Fabin Dang, Li Nie, Jin Zhou, Kouhei Shimizu, Chen Chu, Zhong Wu, Anne Fassl, Shizhong Ke, Yuangao Wang, Jinfang Zhang, Tao Zhang, Zhenbo Tu, Hiroyuki Inuzuka, Piotr Sicinski, Adam J. Bass () and Wenyi Wei ()
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Fabin Dang: Beth Israel Deaconess Medical Center, Harvard Medical School
Li Nie: Beth Israel Deaconess Medical Center, Harvard Medical School
Jin Zhou: West China Hospital, Sichuan University
Kouhei Shimizu: Beth Israel Deaconess Medical Center, Harvard Medical School
Chen Chu: Blavatnik Institute, Harvard Medical School
Zhong Wu: Dana-Farber Cancer Institute, Harvard Medical School
Anne Fassl: Blavatnik Institute, Harvard Medical School
Shizhong Ke: Beth Israel Deaconess Medical Center, Harvard Medical School
Yuangao Wang: Boston Children’s Hospital
Jinfang Zhang: Beth Israel Deaconess Medical Center, Harvard Medical School
Tao Zhang: Beth Israel Deaconess Medical Center, Harvard Medical School
Zhenbo Tu: Beth Israel Deaconess Medical Center, Harvard Medical School
Hiroyuki Inuzuka: Beth Israel Deaconess Medical Center, Harvard Medical School
Piotr Sicinski: Blavatnik Institute, Harvard Medical School
Adam J. Bass: Dana-Farber Cancer Institute, Harvard Medical School
Wenyi Wei: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25700-6

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