Selection for targeted therapy resistance leads to an indirect selection for higher phenotypic plasticity and enhanced evolvability to orthogonal stressors

Acquired resistance to targeted therapies is the primary barrier to durable cancer remission. Therapy resistance is often associated with stemness and intermediate EMT programs, which are often viewed as proximal resistance mechanisms. On the other hand, a growing body of evidence suggests that these programs facilitate resistance through plasticity-mediated adaptations. Integrating computational modeling, functional experimental assays, and lineage tracing, we investigated the relationship between EMT and therapy resistance in experimental models of acquired resistance to ALK+ lung cancer. Our results support a model where phenotypic plasticity, associated with intermediate EMT, is a selectable trait, and selection for subpopulations with higher phenotypic plasticity is amplified under a multifactorial resistance scenario. Consequently, resistance to targeted therapy is associated with higher ability to adapt to orthogonal therapeutic and environmental stressors, as well as higher metastatic potential. These findings identify cellular plasticity as the fundamental substrate from which multifactorial resistance and metastatic competence evolve, indicating that targeting phenotypic plasticity can suppress the acquisition of resistance and prolong therapeutic responses.