Authors: 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, Wenyi Wei
Published: 2021-09-10
DOI: 10.1038/s41467-021-25700-6
Source: Full article
AbstractAlthough 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.