Mechanistically, our data indicate that ELF1 transcriptionally regulates EGFR and that ERK1/2 interacts with ELF1, suggesting the existence of a positive ELF1/EGFR/ERK feedback loop that sustains resistance. This study elucidates a possible mechanism of resistance to AR inhibition driven by an ELF1/EGFR/ERK feedback loop in AR-Vs positive cells and provides a rationale for combining EGFR inhibitors with AR-targeted therapy as a potential treatment strategy for patients with advanced, enzalutamide-resistant prostate cancer.

Additionally, it mitigated the hepatotoxic effects of flutamide. Therefore, this combination may represent a new treatment strategy for PCa.

P1, N=36, Completed, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Completed | N=18 --> 36

Leveraging these insights, we perform structure-based virtual screening based on the identified druggable conformations and identify K53, a rationally designed AR-NTD antagonist, which exhibits potent anti-proliferative activity in enzalutamide-resistant prostate cancer cells. K53 directly binds the AR-NTD, suppresses AR transcriptional activity, and demonstrates high selectivity for cancer cells. This work provides a rational design paradigm for targeting intrinsically disordered proteins and offers a therapeutic candidate for resistant prostate cancer.

P2, N=132, Recruiting, University Health Network, Toronto | Trial completion date: Mar 2026 --> Feb 2031 | Trial primary completion date: Mar 2026 --> Feb 2031

P2, N=100, Recruiting, Region Stockholm

APOL3 is a central driver of PCa aggressiveness and enzalutamide resistance, functioning via the direct modulation of the DAB2IP/STAT3 axis and the activation of the GR bypass pathway. Cotargeting APOL3 alongside DAB2IP restoration represents a highly promising, synergistic therapeutic strategy to circumvent adaptive resistance and halt metastatic progression in advanced castration-resistant prostate cancer.

Talazoparib added to enzalutamide led to significantly better imaging-based progression-free survival than placebo plus enzalutamide among patients with metastatic APMS prostate cancer harboring alterations in homologous recombination repair genes. Serious adverse events were more common with talazoparib plus enzalutamide than with placebo plus enzalutamide. (Funded by Pfizer; TALAPRO-3 ClinicalTrials.gov number, NCT04821622.).

P2, N=23, Recruiting, Martin T. King, MD, PhD | Not yet recruiting --> Recruiting

Collectively, our findings implicate Kaiso as a key player in TNBC and QNBC, highlighting its potential as a druggable target for improving outcomes in these aggressive breast cancer subtypes.

To antagonize the ACSL4-conferred ferroptosis risk, SCL/NEL cells upregulated GPX4 through AP-1 transcription complex to suppress ferroptosis and thus promoted the malignant progression of SCL/NEL cells. Notably, we characterized Auranofin, an anti-rheumatoid arthritis drug, as a ferroptosis inducer for these SCL/NEL cells in vitro and in vivo by targeting AP-1 and decreasing GPX4 expression, suggesting a new application for Auranofin in treating enzalutamide-resistant stem cell-like AP-1High CRPC.

P2, N=66, Active, not recruiting, Sir Mortimer B. Davis - Jewish General Hospital | Recruiting --> Active, not recruiting | Trial completion date: Nov 2027 --> Nov 2030 | Trial primary completion date: Nov 2027 --> Nov 2030