Targeting nuclear EGFR and AURKA as a therapy for anti-androgen resistance in TP53- and RB1-deficient prostate cancer

Resistance to newer anti-androgen drugs such as enzalutamide and abiraterone that are currently used for patients with advanced prostate cancer is an emerging clinical problem. The objective of the proposed research is to understand the mechanisms involved in the development of castration-resistant prostate cancer (CRPC) and the acquisition of resistance to anti-androgen drugs, with the ultimate goal of identifying rational therapeutic approaches to overcome this resistance. The significance of epidermal growth factor receptor (EGFR) tyrosine kinase in the progression to castration resistant disease is suggested by studies showing aberrantly activated EGFR in CRPC clinical samples. However, clinical trials using EGFR tyrosine kinase inhibitors (TKIs) have not shown efficacy in patients with CRPC. Nuclear localization of EGFR has been implicated in enhanced resistance to EGFR targeted therapies, as nuclear EGFR (nEGFR) has kinase-independent functions. Recently, we made the striking observation in patient-derived xenograft (PDX) and transgenic models of prostate cancer that nEGFR is strongly induced during the transition to CRPC and enzalutamide resistance. We propose to develop a small molecule EGFR degrader as a strategy to abrogate nEGFR function and reverse therapeutic resistance in prostate cancer. Successful completion of these studies will provide novel biological insight into anti-androgen therapy resistance in prostate cancer, a new chemical tool for probing nEGFR function, as well as a possible therapeutic lead for treating high nEGFR-expressing tumors.