JNJ-64619178 radiosensitizes and suppresses fractionated ionizing radiation-induced neuroendocrine differentiation (NED) in prostate cancer

Background: Radiation therapy (RT) is a standard treatment regimen for locally advanced prostate cancer; however, its failure results in tumor recurrence, metastasis, and cancer-related death. The recurrence of cancer after radiotherapy is one of the major challenges in prostate cancer treatment. Despite overall cure rate of 93.3% initially, prostate cancer relapse in 20-30% patients after radiation therapy. Cancer cells acquire radioresistance upon fractionated ionizing radiation (FIR) treatment, eventually undergo neuroendocrine differentiation (NED) and transform into neuroendocrine-like cells, a mechanism involved in acquiring resistance to radiation therapy. Radiosensitizers are agents that inhibit the repair of radiation-induced DNA damage. Protein arginine methyltransferase 5 (PRMT5) gets upregulated upon ionizing radiation treatment and epigenetically activates DNA damage repair genes in prostate cancer cells. In this study, we targeted PRMT5 with JNJ-64619178 and assessed its effect on DNA damage repair gene activation, radiosensitization, and FIR-induced NED in prostate cancer.

Methods: γH2AX foci analysis was performed to evaluate the DNA damage repair after radiation therapy. RT-qPCR and western blot were carried out to analyze the expression of DNA damage repair genes. Clonogenic assay was conducted to find out the surviving fraction after radiation therapy. NED was targeted with JNJ-64619178 in androgen receptor (AR) positive and negative prostate cancer cells undergoing FIR treatment.

Results: JNJ-64619178 inhibits DNA damage repair in prostate cancer cells independent of their AR status. JNJ-64619178 impairs the repair of ionizing radiation-induced damaged DNA by transcriptionally inhibiting the DNA damage repair gene expression and radiosensitizes prostate, glioblastoma and lung cancer cell line. It targets NED induced by FIR in prostate cancer cells.

Conclusion: JNJ-64619178 can radiosensitize and suppress NED induced by FIR in prostate cancer cells and can be a potential radiosensitizer for prostate cancer treatment.

 

Comments:

The study you described aimed to investigate the potential of JNJ-64619178, a targeted inhibitor of protein arginine methyltransferase 5 (PRMT5), as a radiosensitizer for prostate cancer treatment. The researchers focused on the problem of tumor recurrence and metastasis following radiation therapy, which remains a major challenge in the treatment of locally advanced prostate cancer.

The researchers found that cancer cells acquire radioresistance after fractionated ionizing radiation (FIR) treatment, leading to tumor recurrence. One mechanism involved in this radioresistance is the transformation of cancer cells into neuroendocrine-like cells through a process called neuroendocrine differentiation (NED). The activation of DNA damage repair genes by PRMT5 plays a role in this process.

To evaluate the potential of JNJ-64619178 as a radiosensitizer, the researchers performed various experiments. They analyzed the repair of radiation-induced DNA damage using γH2AX foci analysis and found that JNJ-64619178 inhibited DNA damage repair in prostate cancer cells, regardless of their androgen receptor (AR) status. This inhibition was achieved by transcriptionally inhibiting the expression of DNA damage repair genes.

Furthermore, the researchers conducted clonogenic assays to determine the surviving fraction of cancer cells after radiation therapy. They observed that JNJ-64619178 radiosensitized prostate cancer cells, as well as glioblastoma and lung cancer cell lines, indicating its potential as a radiosensitizer for various types of cancer.

Additionally, the researchers investigated the effect of JNJ-64619178 on FIR-induced NED in prostate cancer cells. They found that JNJ-64619178 targeted the process of NED induced by FIR, further highlighting its potential as a therapeutic agent for preventing tumor recurrence and metastasis.

In conclusion, the study suggests that JNJ-64619178 can inhibit DNA damage repair, radiosensitize prostate cancer cells, and suppress NED induced by FIR. These findings indicate that JNJ-64619178 has the potential to be a promising radiosensitizer for the treatment of prostate cancer.

Related Products

Cat.No.	Product Name	Information
S8624	Onametostat (JNJ-64619178)	Onametostat (JNJ-64619178) is a PRMT5 inhibitor with high selectivity and potency (subnanomolar range, PRMT5-MEP-50 IC50=0.14 nM) under different in vitro and cellular conditions, paired with favorable pharmacokinetics and safety properties.

Related Targets

PRMT Histone Methyltransferase