Resisting Resistance: Targeted Therapies in Lung Cancer

Drug resistance inevitably limits the efficacy of all targeted therapies including tyrosine kinase inhibitors (TKIs). Understanding the biological underpinnings of TKI resistance is key to the successful development of future therapeutic strategies. Traditionally, mechanisms of TKI resistance have been viewed under a dichotomous lens. Tumor cells are TKI-sensitive or TKI-refractory, exhibit intrinsic or acquired resistance, and accumulate alterations within or outside the target to promote their survival. Such classifications facilitate our comprehension of an otherwise complex biology, but are likely an oversimplification. Recent studies underscore the multifaceted, genetically heterogeneous nature of TKI resistance, which evolves dynamically with changes in therapy. In this Review, we provide a broad framework for understanding the diverse mechanisms of resistance at play in oncogene-driven lung cancers.