Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression

Yueh-Te Lin; Joseph Lin; Yi-En Liu; Kai-Wen Hsu; Chang-Chi Hsieh; Dar-Ren Chen; Han-Tsang Wu

doi:10.1016/j.tranon.2021.101302

Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression

Transl Oncol. 2022 Jan;15(1):101302. doi: 10.1016/j.tranon.2021.101302. Epub 2021 Dec 7.

Authors

Yueh-Te Lin¹, Joseph Lin², Yi-En Liu³, Kai-Wen Hsu⁴, Chang-Chi Hsieh⁵, Dar-Ren Chen⁶, Han-Tsang Wu⁷

Affiliations

¹ Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Gueishan Dist., Taoyuan 333, Taiwan.
² Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan.
³ Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan.
⁴ Research Center for Cancer Biology, Institute of New Drug Development, China Medical University, Taichung 404, Taiwan.
⁵ Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan.
⁶ Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan. Electronic address: darren_chen@cch.org.tw.
⁷ Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan. Electronic address: 182033@cch.org.tw.

Abstract

Breast cancer is common worldwide, and the estrogen receptor-positive subtype accounts for approximately 70% of breast cancer in women. Tamoxifen and fulvestrant are drugs currently used for endocrinal therapy. Breast cancer exhibiting endocrine resistance can undergo metastasis and lead to the death of breast cancer patients. Drug repurposing is an active area of research in clinical medicine. We found that nafamostat mesylate, clinically used for patients with pancreatitis and disseminated intravascular coagulation, acts as an anti-cancer drug for endocrine-resistant estrogen receptor-positive breast cancer (ERPBC). Epigenetic repression of CDK4 and CDK6 by nafamostat mesylate induced apoptosis and suppressed the metastasis of ERPBC through the deacetylation of Histone 3 Lysine 27. A combination of nafamostat mesylate and CDK4/6 inhibitor synergistically overcame endocrine resistance in ERPBC. Nafamostat mesylate might be an essential adjuvant or alternative drug for the treatment of endocrine-resistant ERPBC due to the low cost-efficiency of the CDK4/6 inhibitor.

Keywords: CDK4/6; Endocrine resistance; Estrogen receptor-positive breast cancer; Nafamostat mesylate.