Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives

SIMPLE SUMMARY: The poor survival of unresectable locally advanced stage non-small cell lung cancer is due to the resistance to chemoradiotherapy and local/distant relapses. However, with the advent of new drugs, it has become possible to improve the prognosis of patients with stage III NSCLC harboring certain genetic mutations. Herein, we review new therapeutic strategies to overcome this radioresistance with drugs targeting cancer stem cells/specific mutations or new radiotherapy modalities. ABSTRACT: Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.