The role of USP27X-Cyclin D1 axis in HER2 Therapy Resistant Breast Cancer

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PROJECT SUMMARY/ABSTRACT Overexpression of Cyclin D1 (CCND1) is recognized as a major resistance mechanism to HER2 targeting agents. Patients with CCND1 amplification have the worst response to trastuzumab-containing therapy, and CCND1 overexpression is enough to render cancer cells insensitive to HER2 inactivation. Furthermore, tumors that evade HER2 targeted therapy by reducing HER2 expression rely on CCND1 overexpression and are extremely sensitive to its ablation. Thus, targeting CCND1 is a promising strategy for overcoming resistance to HER2-targeting agents in breast cancer patients. Although CCND1 itself is not a druggable target, this protein has a rapid turnover, and its steady-state level in cells is tightly regulated by ubiquitin-mediated degradation. Perturbation of CCND1 deubiquitination accelerates its degradation. We have recently discovered a novel, previously uncharacterized deubiquitinating enzyme – USP27X, whose higher expression significantly correlates with poor survival of HER2 positive breast cancer patients. Importantly, our studies identify USP27X as a critical regulator of CCND1 protein stability in HER2 therapy-resistant breast cancer cells. Ablation of USP27X severely reduces xenograft tumor growth and significantly increases cell sensitivity to HER2 and CDK4/6 inhibitors. We hypothesize that USP27X can be a key therapeutic target in HER2 therapy-resistant or recurrent breast cancer through CCND1 degradation. This project focuses on understanding the functions of USP27X in CCND1 regulation and elucidating the roles of this deubiquitinating enzyme in cancer development and progression. We will utilize several engineered cell lines as well as a novel and clinically relevant mouse model carrying a conditional Usp27X allele to 1) Elucidate the molecular mechanism underlying the reduced CCND1 steady-state levels in USP27X ablated cells 2) Determine how the loss of USP27X will affect tumor development and progression in vivo, and 3) Define how abrogation of USP27X activity alters the therapeutic response of HER2 therapy-resistant cells to HER2 inhibition. USP27X is a druggable target, and our studies will illuminate new avenues for therapeutic intervention in HER2 therapy-resistant and CCND1 dependent cancers. Although there are no USP27X specific inhibitors currently available, the studies proposed in this project are essential for establishing this deubiquitinating enzyme as a drug target as they will provide a rationale for developing USP27X specific inhibitors.