1. Academic Validation
  2. CDKL3 is a targetable regulator of cell cycle progression in cancers

CDKL3 is a targetable regulator of cell cycle progression in cancers

  • J Clin Invest. 2024 Jul 4:e178428. doi: 10.1172/JCI178428.
Haijiao Zhang 1 Jiahui Lin 1 Shaoqin Zheng 1 Lanjing Ma 1 Zhongqiu Pang 1 Hongyi Yin 1 Chengcheng Meng 2 Yinuo Wang 1 Qing Han 1 Xi Zhang 1 Zexu Li 1 Liu Cao 3 Lijun Liu 1 Teng Fei 1 Daming Gao 4 Liang Yang 5 Xueqiang Peng 5 Chen Ding 1 Shixue Wang 6 Ren Sheng 1
Affiliations

Affiliations

  • 1 College of Life and Health Sciences, Northeastern University, Shenyang, China.
  • 2 Department of Pathology, The Fourth People's Hospital of Shenyang, Shenyang, China.
  • 3 Key Laboratory of Medical Cell Biology, China Medical University, Shenyang, China.
  • 4 State Key Laboratory of Cell Biology, Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of General Surgery, China Medical University, Shenyang, China.
  • 6 State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, Changchun, China.
Abstract

Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essentially meaningful. Here, we identified an under-appreciated Serine/Threonine kinase, CDKL3 (Cyclin-dependent kinase like 3), crucially drives the rapid cell cycle progression and cell growth in cancers. Mechanism-wise, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate Retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of CDK4 by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 (Cyclin-dependent kinase 4/6) inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes the acquired resistance of the latter. In particular, CDKL3 has significant clinical relevance in colon Cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived Cancer Models. Collectively, this work presented an integrated paradigm of Cancer cell cycle regulation and suggested CDKL3-targeting as a feasible approach in Cancer treatment.

Keywords

Cancer; Cell biology; Cell cycle; Drug therapy; Therapeutics.

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