Open AccessA YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components
Author(s) -
Monique B. Nilsson,
Huiying Sun,
Jacqulyne P. Robichaux,
Matthias Pfeifer,
Ultan McDermott,
Jon Travers,
Lixia Diao,
Yuanxin Xi,
Pan Tong,
Ли Шен,
Mia Hofstad,
Masanori Kawakami,
Xiuning Le,
Xi Liu,
You-Hong Fan,
Alissa Poteete,
Limei Hu,
Marcelo V. Negrão,
Hai T. Tran,
Ethan Dmitrovsky,
David H. Peng,
Don L. Gibbons,
Jing Wang,
John V. Heymach
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaz4589
Subject(s) - foxm1 , microbiology and biotechnology , cancer research , chemistry , cell cycle checkpoint , spindle checkpoint , biology , cell cycle , spindle apparatus , biochemistry , cell , cell division
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.