Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies

The discovery of <i>EGFR</i> mutations two decades ago launched an era of rapid development and clinical application of targeted therapies in NSCLC. Today, increasing numbers of targeted therapies against somatic aberrations involving nine different genes have become available for treating patients with lung cancer and have improved their outcomes. However, acquired resistance and tumor tolerance to these therapies remains one of the biggest challenges in lung cancer treatment today. Most, if not all, targeted therapies have limited durability, which we now recognize is due to both genetic and non-genetic mechanisms of resistance. The state of our current understanding of resistance and new approaches to prevent or overcome resistance were recently presented at the International Association for the Study of Lung Cancer Hot Topics Meeting. Here, we summarize and discuss the emerging concepts and new strategies for combating drug tolerance and resistance in targeted therapies, including our understanding of the role of genetics, drug-tolerant persister cells, tumor plasticity and lineage transformation, spatial and temporal heterogeneity, microenvironmental influence, and novel therapeutic approaches.