Selection for Targeted Therapy Resistance Indirectly Selects for Cancer Cells with Enhanced Phenotypic Plasticity and Evolvability to Orthogonal Stressors.

In non-small cell lung cancer, ALK inhibitor resistance is linked to progressively enriched phenotypic plasticity, with higher adaptation potential tied to increased metastatic potential and chromatin accessibility at EMT/stemness regulators.

• Why it matters: Resistance to targeted therapies is often associated with stem-like and partial EMT programs, but it is unclear whether these programs directly cause resistance or instead mark broader plasticity that enables escape.
• What they did: The study combined computational modeling with experimental validation across multi-step ALK inhibitor resistance trajectories, using lineage tracing and clonal analyses to quantify heritable intra-cell variability in adaptation potential and test links to chromatin accessibility.
• The result: Cells with higher adaptation potential showed increased chromatin accessibility at EMT/stemness regulators, and adaptation potential was increased by inducing stemness/EMT programs while SOX2 knockdown or epigenetic inhibition suppressed it, with corresponding resistance effects.

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