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

Keywords: chemotherapy; hypoxia; immunotherapy; lung cancer; radiotherapy; targeted therapy; therapeutic resistance; tumor microenvironment.

Figure 1

The treatment options for lung cancer are surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy (created with BioRender.com (accessed on 1 September 2022).

Figure 2

Different mechanisms inducing therapeutic resistance in lung cancer: Therapeutic resistance against chemotherapy, radiotherapy, targeted therapy, and immunotherapy in lung cancer is caused by different types of mechanism. For instance, tumor heterogeneity, alteration in drug influx and efflux, compartmentalization, epigenetic changes, hypoxia, or reduced autophagy stimulate chemoresistance in lung cancer. Radioresistance is found to happen by epithelial and mesenchymal transition, DNA damage, dysregulated miRNA, and changes in various signaling pathways. Mutations in EGFR or KRAS genes and targets as well as alterations in drug sensitivity lead to mutations at T790M that cause primary and acquired resistance for targeted therapy. Mutations in cancer driver genes, immunosuppressive TME, modified epigenetics, and high bioenergetic are mainly responsible for triggering immunoresistance in lung cancer (created with BioRender.com (accessed on 15 September 2022).