Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence

Cancers

Sohyun Hwang¹  Kyung-Soon Park¹  Hee-Jung An²  Sewha Kim²  Kamal Pandey³  Minsil Kang³  Nahee Park³  Jin Hur³  YongWha Moon³  YongBin Cho³ 

[1] Department of Biomedical Science, CHA University, Seongnam 13488, Korea;Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea;Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea;

关键词: CDK4/6;    CDK2;    hormone receptor-positive breast cancer;    drug resistance;    C-MYC;   

DOI  :  10.3390/cancers12123566

来源: DOAJ

【 摘 要 】

Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.

【 授权许可】

Unknown