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

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

doi:10.3389/fphar.2021.614673

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.

Highlights

Breast cancer is the most common cancer type and ranks second among causes for cancer death in women (Fahad Ullah, 2019)
To address whether Pim1 regulates HER family expression in breast cancer, we first examined the association between Pim1 and HER family protein expressions using a panel of breast cancer cell lines by western blot (Figure 1A)
We found that the IC50 of SMI-4a significantly and inversely correlated with EGFR, HER2, and HER3 protein levels while the IC50 of SGI-1776 only significantly and negatively correlated with EGFR and HER2 protein level (Figure 2C)

Summary

Introduction

Breast cancer is the most common cancer type and ranks second among causes for cancer death in women (Fahad Ullah, 2019). According to the expression pattern of biomarkers, including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2, known as Neu, ErbB2, EGFR2), breast cancer can be classified into several subtypes (Raica et al, 2009). Among these biomarkers, HER2 overexpression is correlated with poor prognosis prior to the advent of anti-HER2 therapies (Barros et al, 2010; Santa-Maria et al, 2016).

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Results

Conclusion