Research ArticleCancer

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

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Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaaq1238
DOI: 10.1126/scitranslmed.aaq1238

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Lung cancer finding its sensitive side

Mutations in an oncogene called KRAS are common in a variety of tumor types, including lung cancer, and these tumors are often difficult to treat. In addition to tumor genetics, tumor cell phenotype plays a role in treatment resistance, and tumor cells that have converted from an epithelial to a mesenchymal phenotype are less likely to respond to chemotherapy. Peng et al. examined signaling alterations that occur during the epithelial-to-mesenchymal transition and identified a pathway that could be targeted by the epigenetic drug mocetinostat, restoring sensitivity to chemotherapy in cancer cells and mouse models.

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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