Novel Therapy Strategies for Mesenchymal Non-Small Cell Lung Cancer
Abstract
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 resistant/epithelial NSCLC cell lines and inhibited in sensitive/mesenchymal 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2018
- Accession Number
- AD1058227
Entities
People
- Faye M Johnson
Organizations
- University of Texas at Austin