2. Academic Validation
  3. Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer

  • MedComm (2020). 2024 Apr 13;5(4):e537. doi: 10.1002/mco2.537.
Yinan Jiang 1,  Shuting Huang 2,  Lan Zhang 3,  Yun Zhou 1,  Wei Zhang 4,  Ting Wan 1,  Haifeng Gu 1,  Yi Ouyang 5,  Xiaojing Zheng 1,  Pingping Liu 1,  Baoyue Pan 1,  Huiling Xiang 1,  Mingxiu Ju 1,  Rongzhen Luo 6,  Weihua Jia 7,  Shenjiao Huang 8,  Jundong Li 1,  Min Zheng 1
Affiliations

Affiliations

  • 1 Department of Gynecology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China.
  • 2 Department of Gynecology, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou China.
  • 3 Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital Yunnan Cancer Center Kunming China.
  • 4 Department of Clinical Immunology, The Third Affiliated Hospital Sun Yat-sen University Guangzhou China.
  • 5 Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China.
  • 6 Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China.
  • 7 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China.
  • 8 Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou China.
PMID: 38617434 DOI: 10.1002/mco2.537
Abstract

Platinum resistance represents a major barrier to the survival of patients with ovarian Cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced Apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast Cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Keywords

Cdc2‐like kinase 2; DNA damage repair; ovarian cancer; platinum resistance; synergistic lethal.

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