@article{a376c579a625491490c27b40ed111ba8,
title = "Dual inhibition of MEK and AXL targets tumor cell heterogeneity and prevents resistant outgrowth mediated by the epithelial-to-mesenchymal transition in NSCLC",
abstract = "The epithelial-to-mesenchymal transition (EMT) is a dynamic epigenetic reprogramming event that occurs in a subset of tumor cells and is an initiating step toward invasion and distant metastasis. The process is reversible and gives plasticity to cancer cells to survive under variable conditions, with the acquisition of cancer stem cell–like characteristics and features such as drug resistance. Therefore, understanding survival dependencies of cells along the phenotypic spectrum of EMT will provide better strategies to target the spatial and temporal heterogeneity of tumors and prevent their ability to bypass single-inhibitor treatment strategies. To address this, we integrated the data from a selective drug screen in epithelial and mesenchymal KRAS/p53 (KP)-mutant lung tumor cells with separate datasets including reverse-phase protein array and an in vivo shRNA dropout screen. These orthogonal approaches identified AXL and MEK as potential mesenchymal and epithelial cell survival dependencies, respectively. To capture the dynamicity of EMT, incorporation of a dual fluorescence EMT sensor system into murine KP lung cancer models enabled real-time analysis of the epigenetic state of tumor cells and assessment of the efficacy of single agent or combination treatment with AXL and MEK inhibitors. Both two- and three-dimensional culture systems and in vivo models revealed that this combination treatment strategy of MEK plus AXL inhibition synergistically killed lung cancer cells by specifically targeting each phenotypic subpopulation. In conclusion, these results indicate that cotargeting the specific vulnerabilities of EMT subpopulations can prevent EMT-mediated drug resistance, effectively controlling tumor cell growth and metastasis. Significance: This study shows that a novel combination of MEK and AXL inhibitors effectively bypasses EMT-mediated drug resistance in KRAS/p53-mutant non–small cell lung cancer by targeting EMT subpopulations, thereby preventing tumor cell survival.",
author = "Konen, {Jessica M.} and Rodriguez, {B. Leticia} and Aparna Padhye and Ochieng, {Joshua K.} and Laura Gibson and Lixia Diao and Fowlkes, {Natalie W.} and Fradette, {Jared J.} and Peng, {David H.} and Cardnell, {Robert J.} and Kovacs, {Jeffrey J.} and Jing Wang and Byers, {Lauren A.} and Gibbons, {Don L.}",
note = "Funding Information: J.J. Kovacs reports a patent for WO2016004418A1 licensed to Ipsen Pharmaceutical. L.A. Byers reports grants and other from AstraZeneca (serves on advisory committee) and GenMab (serves on advisory committee), nonfinancial support and other from BergenBio (serves on advisory committee), and grants from Tolero Pharmaceuticals outside the submitted work. D.L. Gibbons reports grants from NIH, CPRIT, LUNGevity Foundation, and Rexanna's Foundation during the conduct of the study, and has served on scientific advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi, and Janssen and has received research support from Janssen, Takeda, Ribon Therapeutics, Astellas, and AstraZeneca. No disclosures were reported by the other authors. Funding Information: This work was supported in part by NIH grants R37CA214609 (to D.L. Gibbons), R01CA207295 and U01CA213273 (to L.A. Byers), and F32CA239292 (to J.M. Konen). This work was also supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP160652 (to D.L. Gibbons), the University of Texas Lung Cancer SPORE grant P5CA070907, the LUNGevity Foundation award (to L.A. Byers and D.L. Gibbons), Rexanna's Foundation (to L.A. Byers and D.L. Gibbons), and through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. The Flow Cytometry Lab South Campus Core facility at MD Anderson Cancer Center is supported by CCSG NCI P30CA16672. The authors thank BergenBio (Norway) for providing bemcentinib. They thank Dr. Sendurai Mani (MD Anderson Cancer Center, Houston, TX) and Dr. Jeffrey Rosen (Baylor College of Medicine, Houston, TX) for the E-cad RFP and GFP Zeb1 3′UTR expression constructs. The authors thank Dr. John Heymach (MD Anderson Cancer Center, Houston, TX) for providing the GLS inhibitor for their drug screen. They thank the Institute for Applied Cancer Science (IACS at MD Anderson Cancer, Houston, TX) for providing compounds for our drug screen. The authors thank the Flow Cytometry Lab South Campus Core facility at MD Anderson Cancer Center for the use of their facilities. Publisher Copyright: {\textcopyright}2020 American Association for Cancer Research.",
year = "2021",
month = mar,
day = "1",
doi = "10.1158/0008-5472.CAN-20-1895",
language = "English (US)",
volume = "81",
pages = "1398--1412",
journal = "Cancer Research",
issn = "0008-5472",
number = "5",
}