A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components

• DOI: 10.1126/scitranslmed.aaz4589
• Publication Date: 2020-09-02T23:10:16Z
• Authors: Monique B. Nilsson; Huiying Sun; Jacqulyne Robichaux; Matthias Pfeifer; Ultan McDermott; Jon Travers; Lixia Diao; Yuanxin Xi; Pan Tong; Li Shen; Mia Hofstad; Masanori Kawakami; Xiuning Le; Xi Liu; Youhong Fan; Alissa Poteete; Limei Hu; Marcelo V. Negrao; Hai Tran; Ethan Dmitrovsky; David Peng; Don L. Gibbons; Jing Wang; John V. Heymach
• Keywords: FOXM1

Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which emerges through EGFR-independent mechanisms, such as pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation the yes-associated protein (YAP) forkhead box M1 (FOXM1) axis driver EMT-associated EGFR TKI resistance. inhibitor was associated with broad multidrug extended across multiple chemotherapeutic targeted agents, consistent difficulty effectively treating resistant disease. TKI-resistant cells displayed increased abundance spindle assembly checkpoint (SAC) proteins, including polo-like 1 (PLK1), Aurora kinases, survivin, kinesin (KSP). Moreover, exhibited vulnerability SAC inhibitors. Increased YAP/FOXM1 mediated increase components cells. The relevance these finding indicated by evaluation specimens from patients mutant lung cancer, showed high FOXM1 expression correlated genes encoding proteins worse outcome. These data revealed central regulator this pathway, along components, therapeutic vulnerabilities for targeting multidrug-resistant phenotype.