Novel Therapy Strategies for Mesenchymal Non-Small Cell Lung Cancer
Technical Report,01 Jul 2017,30 Jun 2018
University of Texas MD Anderson Cancer Center Houston United States
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We discovered that mesenchymal non-small cell lung cancer NSCLC cells were more sensitive to polo-like kinase PLK1 inhibitors than epithelial cell lines. Additionally cMet and FAK were activated in resistantepithelial NSCLC cell lines and inhibited in sensitivemesenchymal lines following PLK1 inhibition. We hypothesize that mesenchymal NSCLC will undergo apoptosis following PLK1 inhibition in vivo but that activation of cMet will mediate resistance in epithelial NSCLC. We have made significant progress in testing this hypothesis. Treatment in four patient derived xenograft models demonstrated that the PLK1 inhibitor volasertib was more effective in the mesenchymal models. Likewise volasertib was more effective in the mesenchymal orthotopic NSCLC model than in its isogenic epithelial pair. We found a similar degree of epithelial to mesenchymal transition EMT within each NSCLC tumor but considerable intra-tumor EMT heterogeneity. We discovered that cMet was the upstream regulator of FAK that was driving resistance in the epithelial NSCLC. Combination studies with cMet and PLK1 inhibitors showed significant apoptosis in all NSCLC models tested. Overexpression of constitutively active cMet led to resistance to PLK1 inhibitors. In conclusion, our research supports our hypothesis, we are ahead of our planned schedule, and we anticipate that we will complete the project as proposed.
- Medicine and Medical Research