Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability.

Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) in vitro. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli in vivo. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy.