TY - JOUR
T1 - A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components
AU - Nilsson, Monique B.
AU - Sun, Huiying
AU - Robichaux, Jacqulyne
AU - Pfeifer, Matthias
AU - McDermott, Ultan
AU - Travers, Jon
AU - Diao, Lixia
AU - Xi, Yuanxin
AU - Tong, Pan
AU - Shen, Li
AU - Hofstad, Mia
AU - Kawakami, Masanori
AU - Le, Xiuning
AU - Liu, Xi
AU - Fan, Youhong
AU - Poteete, Alissa
AU - Hu, Limei
AU - Negrao, Marcelo V.
AU - Tran, Hai
AU - Dmitrovsky, Ethan
AU - Peng, David
AU - Gibbons, Don L.
AU - Wang, Jing
AU - Heymach, John V.
N1 - Funding Information:
This work was funded by LUNGevity Foundation, Lung SPORE grant 5 P50 CA070907 (to J.V.H.), Lung Cancer Moon Shot Program, NIH CCSG (CA016672) (to J.V.H.), 1R01 CA190628 (to J.V.H.), the Rexanna Foundation for Fighting Lung Cancer, Bruton Endowed Chair in Tumor Biology, Stading Fund for EGFR inhibitor resistance, the Fox Lung EGFR Inhibitor Fund, the Hanlon Fund, the Hallman Fund, and the Kopelman Foundation
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved;
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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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U2 - 10.1126/SCITRANSLMED.AAZ4589
DO - 10.1126/SCITRANSLMED.AAZ4589
M3 - Article
C2 - 32878980
AN - SCOPUS:85090261318
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 559
M1 - eaaz4589
ER -