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Sci Transl Med. 2019 Mar 13;11(483). pii: eaaq1238. doi: 10.1126/scitranslmed.aaq1238.

ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism.

Author information

1
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
3
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine and Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
6
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. dlgibbon@mdanderson.org.
9
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract

Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors have failed to show clinical benefit in Kirsten rat sarcoma (KRAS) mutant lung cancer due to various resistance mechanisms. To identify differential therapeutic sensitivities between epithelial and mesenchymal lung tumors, we performed in vivo small hairpin RNA screens, proteomic profiling, and analysis of patient tumor datasets, which revealed an inverse correlation between mitogen-activated protein kinase (MAPK) signaling dependency and a zinc finger E-box binding homeobox 1 (ZEB1)-regulated epithelial-to-mesenchymal transition. Mechanistic studies determined that MAPK signaling dependency in epithelial lung cancer cells is due to the scaffold protein interleukin-17 receptor D (IL17RD), which is directly repressed by ZEB1. Lung tumors in multiple Kras mutant murine models with increased ZEB1 displayed low IL17RD expression, accompanied by MAPK-independent tumor growth and therapeutic resistance to MEK inhibition. Suppression of ZEB1 function with miR-200 expression or the histone deacetylase inhibitor mocetinostat sensitized resistant cancer cells to MEK inhibition and markedly reduced in vivo tumor growth, showing a promising combinatorial treatment strategy for KRAS mutant cancers. In human lung tumor samples, high ZEB1 and low IL17RD expression correlated with low MAPK signaling, presenting potential markers that predict patient response to MEK inhibitors.

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