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Novel Therapy Strategies for Mesenchymal Non-Small Cell Lung Cancer

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[Technical Report, Final Report]

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MD Anderson Cancer Center

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Despite therapeutic improvements for non-small cell lung cancer NSCLC, there is still an unmet need for effective systemic therapy. To address this need, we previously demonstrated that mesenchymal NSCLC was sensitive to polo-like kinase 1 PLK1 inhibitors, but the mechanisms of resistance to PLK1 inhibitors in epithelial NSCLC remain unknown. We observed differential regulation of the cMetFAKSrc axis, which is intact in both mesenchymal and epithelial cells. However, PLK1 inhibition inhibits cMet phosphorylation only in mesenchymal NSCLC cells, leading to subsequent inhibition of FAK and Src. Constitutively active cMet abrogates PLK1 inhibitorinduced apoptosis. Likewise, cMet silencing or inhibition enhances PLK1 inhibitorinduced apoptosis. Additionally, cells with acquired resistance to PLK1 inhibitors are more epithelial than their parental cells and maintain cMet activation after PLK1 inhibition. In both patient-derived and cell line xenografts, mesenchymal NSCLC was more sensitive to PLK1 inhibition alone than was epithelial NSCLC. The combination of cMet and PLK1 inhibition led to regression of tumors in three models and marked tumor size reduction in the fourth model. When drug treatment was stopped, tumors treated with the combination did not regrow. PLK1 inhibition did not affect levels of HGF but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via Beta1 integrin. This research defines a heretofore unknown mechanism of ligand-independent activation of cMet downstream of PLK1, as well as an effective combination therapy


Subject Categories:

  • Medicine and Medical Research

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[A, Approved For Public Release]