Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor

Author:

Sawant Mithila,Wilson Audrey,Sridaran DhivyaORCID,Mahajan KiranORCID,O’Conor Christopher J.,Hagemann Ian S.ORCID,Luo JingqinORCID,Weimholt Cody,Li TiandaoORCID,Roa Juan Carlos,Pandey AkhileshORCID,Wu Xinyan,Mahajan Nupam P.ORCID

Abstract

AbstractHormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes,CCNB1, CCNB2andCDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9bdampenedCCNB1, CCNB2andCDC20expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9bsuppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9bcould be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.

Funder

U.S. Department of Defense

U.S. Department of Health & Human Services | NIH | National Cancer Institute

U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Genetics,Molecular Biology

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