N-MYC regulation of DNA damage response in neuroendocrine prostate cancer: mechanistic insight and novel combination therapy approaches

Accumulation of DNA damage leads to genomic instability and can drive cancer progression. Germline and somatic mutations in the BRCA1 or BRCA2 genes can contribute to this genomic instability on the basis of their role in DNA repair. Both BRCA1 and BRCA2 are critical for repair of DNA double-strand breaks by homologous recombination (HR), a conservative form of DNA repair [1]. HR is a critical component of the DNA damage response (DDR) signaling cascade, which detects and propagates DNA damage signals to elicit cellular responses that include cell cycle arrest, DNA repair, and apoptosis. The activities of the DDR signaling cascade are required for DNA-damaged cells to complete the cell cycle, survive and proliferate. Metastatic castration-resistant prostate cancer (CRPC) is associated with increased frequency of germline and somatic DDR gene mutations, including BRCA2, suggesting that DDR targeting therapy provides therapeutic options through synthetic lethal strategies such as poly(ADP-ribose) polymerase (PARP) inhibition [1, 2]. However, CRPC can transition to a more virulent, and poorly differentiated form of the CRPC, i.e., CRPC-Neuro or neuroendocrine prostate cancer (NEPC). Similar to other poorly differentiated neuroendocrine tumors, NEPC can exhibit small cell morphology and neuroendocrine differentiation, and responds poorly to existing therapies [3]