Targeting WEE1 Inhibits Growth of Breast Cancer Cells That Are Resistant to Endocrine Therapy and CDK4/6 Inhibitors

Ayesha N Shajahan-Haq,Wei He,Diane M Demas,Lu Jin,Yassi Fallah

doi:10.3389/fonc.2021.681530

Ayesha N Shajahan-Haq, Wei He + Show 3 more

Open Access

https://doi.org/10.3389/fonc.2021.681530

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Abstract

Despite the success of antiestrogens in extending overall survival of patients with estrogen receptor positive (ER+) breast tumors, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with antiestrogens and CDK4/6 inhibitors. However, 20% of these tumors never respond to CDK4/6 inhibitors due to intrinsic resistance. Here, we used endocrine sensitive ER+ MCF7 and T47D breast cancer cells to generate long-term estrogen deprived (LTED) endocrine resistant cells that are intrinsically resistant to CDK4/6 inhibitors. Since treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest but increases their dependency on G2 checkpoint for DNA repair and growth, and hence, targeting the G2 checkpoint will induce cell death. Indeed, inhibition of WEE1, a crucial G2 checkpoint regulator, with AZD1775 (Adavosertib), significantly decreased cell proliferation and increased G2/M arrest, apoptosis and gamma-H2AX levels (a marker for DNA double stranded breaks) in resistant cells compared with sensitive cells. Thus, targeting WEE1 is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.

Highlights

The majority of breast tumors are estrogen receptor alpha positive (ER+) and are clinically treated with endocrine therapy to deprive tumor cells of estrogen using aromatase inhibitors (AI) or to target the ER using tamoxifen or fulvestrant
The development of highly selective, orally available and ATP competitive cyclin-dependent kinase 4 (CDK4)/6 inhibitors, palbociclib, ribociclib and Intrinsic Resistance to CDK4/6 Inhibitors abemaciclib has transformed the standard of care of ER+ and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer based on prolonged progression-free survival (PFS) when they are combined with antiestrogen therapies [6,7,8]
To compare the sensitivity of long-term estrogen deprived (LTED) and parental cells to CDK4/6 inhibitors, we treated the cells with either vehicle or increasing concentrations of each of the three CDK4/6 inhibitors: palbociclib, ribociclib or abemaciclib (Figures 2A–F)

Summary

Introduction

The majority of breast tumors are estrogen receptor alpha positive (ER+) and are clinically treated with endocrine therapy to deprive tumor cells of estrogen using aromatase inhibitors (AI) or to target the ER using tamoxifen or fulvestrant. The development of highly selective, orally available and ATP competitive CDK4/6 inhibitors, palbociclib, ribociclib and Intrinsic Resistance to CDK4/6 Inhibitors abemaciclib has transformed the standard of care of ER+ and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer based on prolonged progression-free survival (PFS) when they are combined with antiestrogen therapies [6,7,8]. 20% of patients who progress on endocrine therapies show de novo or intrinsic resistance to CDK4/6 inhibitors and tumors that initially respond eventually acquire resistance to the combined therapies [9, 10]. Our knowledge of how breast cancer cells develop resistance to CDK4/6 inhibitors is incomplete

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