Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.

BackgroundAntibody–drug conjugates (ADC), such as enfortumab vedotin (EV), sacituzumab govitecan (SG), and RC-48, have shown outstanding response rates to local advanced or metastatic urothelial carcinoma (UC). However, their corresponding target expression characteristics in UC and its histologic variants were unknown.MethodsWe detected the expression of NECTIN-4, TROP-2, and HER2, which are the corresponding targets of ADCs EV, SG, and RC-48 in muscle-invasive UC through immunohistochemistry.Results161 consecutive samples from 2017 to 2021 of muscle-invasive UC and its histologic variants were obtained in Peking University First Hospital. Variant histology types included 72UC, 10 squamous carcinomas, 23 glandular carcinomas, 19 small cell carcinomas, 19 micropapillary variants, and 18 nested variants. NECTIN-4 expression was found to be 57/72 (79.2%), 10/10 (100%), 15/23 (65.2%), 4/19 (21.1%), 15/19 (78.9%), and 16/18 (88.9%) in conventional UC, squamous carcinoma, glandular carcinoma, small cell carcinoma, micropapillary, and nested variant, respectively, compared with 65/72 (90.3%), 8/10 (80.0%), 13/23 (56.5%), 3/19 (15.8%), 16/19 (84.2%), and 15/18 (83.3%) of TROP-2, and 26/72 (36.1%), 0, 5/23 (21.7%), 6/19 (31.6%), 5/19 (26.3%), and 7/18 (38.9%) of HER2.

Background In response to therapeutic treatments, cancer cells can exhibit a variety of resistance phenotypes including neuroendocrine differentiation (NED). NED is a process by which cancer cells can transdifferentiate into neuroendocrine‐like cells in response to treatments, and is now widely accepted as a key mechanism of acquired therapy resistance. Recent clinical evidence has suggested that non‐small cell lung cancer (NSCLC) can also transform into small cell lung cancer (SCLC) in patients treated with EGFR inhibitors. However, whether chemotherapy induces NED to confer therapy resistance in NSCLC remains unknown. Methods We evaluated whether NSCLC cells can undergo NED in response to chemotherapeutic agents etoposide and cisplatin. By Knock‐down of PRMT5 or pharmacological inhibition of PRMT5 to identify its role in the NED process. Results We observed that both etoposide and cisplatin can induce NED in multiple NSCLC cell lines. Mechanistically, we identified protein arginine methyltransferase 5 (PRMT5) as a critical mediator of chemotherapy‐induced NED. Significantly, the knock‐down of PRMT5 or pharmacological inhibition of PRMT5 suppressed the induction of NED and increased the sensitivity to chemotherapy. Conclusion Taken together, our results suggest that targeting PRMT5 may be explored as a chemosensitization approach by inhibiting chemotherapy‐induced NED.