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Path of least resistance
Drugs that inhibit the epidermal growth factor (EGFR) are used in a number of cancer types, including lung cancer, but the evolution of resistance to treatment remains a problem. In some cases, resistance emerges through mutations in EGFR itself, but it can also develop through alternate mechanisms, which can be more difficult to overcome. Nilsson et al. focused on one such mechanism of resistance, associated with a change in the phenotype of cancer cells called epithelial-to-mesenchymal transition. This change was associated with resistance to multiple cancer drugs, but the authors identified several therapeutic vulnerabilities in the multidrug-resistant cells.
Abstract
Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended across multiple chemotherapeutic and targeted agents, consistent with the difficulty of effectively treating resistant disease. EGFR TKI–resistant cells displayed increased abundance of spindle assembly checkpoint (SAC) proteins, including polo-like kinase 1 (PLK1), Aurora kinases, survivin, and kinesin spindle protein (KSP). Moreover, EGFR TKI–resistant cells exhibited vulnerability to SAC inhibitors. Increased activation of the YAP/FOXM1 axis mediated an increase in the abundance of SAC components in resistant cells. The clinical relevance of these finding was indicated by evaluation of specimens from patients with EGFR mutant lung cancer, which showed that high FOXM1 expression correlated with expression of genes encoding SAC proteins and was associated with a worse clinical outcome. These data revealed the YAP/FOXM1 axis as a central regulator of EMT-associated EGFR TKI resistance and that this pathway, along with SAC components, are therapeutic vulnerabilities for targeting this multidrug-resistant phenotype.
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