Unlocking the Radiosensitizing Potential of MYC Inhibition in Neuroendocrine Malignancies

The MYC family of transcription factors-comprising c-MYC, N-MYC, and L-MYC-plays a pivotal role in oncogenesis, driving cancer progression and resistance to therapy. While MYC proteins have long been considered challenging drug targets due to their intricate structures, recent advances have led to the development of promising inhibitors. This review explores the role of MYC overexpression in promoting radiation therapy resistance in aggressive neuroendocrine malignancies through multiple mechanisms, including increased tumor cell invasion, enhanced DNA damage repair and oxidative stress management, prosurvival autophagy, survival of circulating tumor cells, angiogenesis, awakening from dormancy, and modulation of chronic inflammation and host immunity. Paradoxically, MYC overexpression can also enhance radiosensitivity in certain cancer cells by driving proapoptotic pathways, such as reactive oxygen species-induced DNA damage that overwhelms cellular repair mechanisms, ultimately leading to cell death. Additionally, we provide a comprehensive summary of direct MYC inhibitors, detailing their current stage of preclinical and clinical development as novel anticancer therapeutics. This review highlights the role of MYC in cancer metastasis and radiation therapy resistance while examining the potential of MYC inhibitors as radiosensitizers in adult and pediatric neuroendocrine malignancies, including small cell lung cancer, large cell neuroendocrine lung cancer, Merkel cell carcinoma, neuroendocrine-differentiated prostate cancer, neuroblastoma, central nervous system embryonal tumors, and medulloblastoma.