HKI-357 inhibits castration-resistant prostate cancer by targeting UBE2C via the AKT signaling pathway

Prostate cancer (PCa) is one of the most common malignancies in the male reproductive system. Most patients develop drug resistance following androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC), which is associated with poor clinical outcomes and prognosis. Conventional therapies, including radiotherapy, chemotherapy, and novel endocrine treatments, have shown limited overall efficacy in CRPC patients. Therefore, there is an urgent need to identify new and effective therapeutic agents for CRPC to improve overall survival rates and quality of life for patients. Using an FDA-approved library of 600 covalent compounds, we identified HKI-357 as a potent inhibitor of CRPC cell viability. In vitro, HKI-357 suppresses CRPC cell growth in a dose-dependent manner and induces apoptosis. Consistent with these findings, in a xenograft model, HKI-357 effectively inhibits PC-3 tumor growth without apparent biotoxicity. By Isothermal titration calorimetry (ITC), ubiquitin-conjugating enzyme E2 C (UBE2C) is predicted as a potential target of HKI-357, which was subsequently validated through cellular thermal shift assay (CETSA) and molecular docking. Treatment with HKI-357 decreased UBE2C expression at both transcriptional and translational levels, with inhibition of the phospho-AKT(P-AKT) pathway. In human, the expression levels of UBE2C are significantly higher in PCa versus normal adjacent tissue. Furthermore, UBE2C, as a target of the androgen receptor (AR), shows upregulation in CRPC. In summary, our research demonstrated that HKI-357 can inhibit CRPC progression by targeting UBE2C via the AKT pathway, revealing a new drug mechanism of action and providing a promising therapeutic candidate for CRPC treatment.