Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

SIMPLE SUMMARY: Despite an initial response to therapy, many lung cancer patients inevitably develop resistance to therapy leading to decreased duration of response and success of treatment. Recent research aims to elucidate mechanisms of resistance in order to improve drug response and treatment outcomes. By utilizing multidisciplinary approaches that target various resistance mechanism, it may be possible to delay development of treatment resistance or even resensitize cancers. This review aims to discuss novel approaches to improve clinical outcomes, delay the occurrence of resistance, and overcome resistance. ABSTRACT: Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.