Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2

Bo-Wei Wang; Chih-Hao Huang; Liang-Chih Liu; Fang-Ju Cheng; Ya-Ling Wei; Yueh-Ming Lin; Yu-Fei Wang; Ching-Ting Wei; Yeh Chen; Yun-Ju Chen; Wei-Chien Huang

doi:10.3389/fphar.2021.614673

Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2

Front Pharmacol. 2021 Jun 29:12:614673. doi: 10.3389/fphar.2021.614673. eCollection 2021.

Authors

Bo-Wei Wang¹, Chih-Hao Huang², Liang-Chih Liu², Fang-Ju Cheng¹, Ya-Ling Wei¹, Yueh-Ming Lin³, Yu-Fei Wang¹, Ching-Ting Wei⁴, Yeh Chen⁵, Yun-Ju Chen^{4

6}, Wei-Chien Huang^{1

7

8

9}

Affiliations

¹ Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
² Division of Breast Surgery, China Medical University Hospital, Taichung, Taiwan.
³ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁴ School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
⁵ Institute of New Drug Development, China Medical University, Taichung, Taiwan.
⁶ Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
⁷ Drug Development Center, China Medical University, Taichung, Taiwan.
⁸ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
⁹ The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.

Abstract

The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.

Keywords: HER2; PIM1; breast cancer; drug resistance; lapatinib.