Novel Therapy Strategies for Mesenchymal Non-Small Cell Lung Cancer
Abstract
The epithelial-to-mesenchymal transition (EMT) is a cellular process first described during embryonic development in which epithelial cells ? which usually exist as a tightly adherent layer of cells -- downregulate their cell-cell contacts and are more mobile. Mesenchymal cancer cells have increased invasiveness and resistance to apoptosis (programmed cell death). EMT is present in about 25% of non-small cell lung cancer (NSCLC) tumors where it mediates resistance to anti-cancer therapy and increased expression of the immune checkpoint ligand PDL1. PDL1 makes cancers more resistant to destruction by the immune system and can be targeted with clinically available drugs that inhibit PD1. We recently discovered that mesenchymal NSCLC cells were more sensitive to inhibitors of the protein polo-like kinase 1 (PLK1) than epithelial cell lines. PLK1 is a key regulator of the cell cycle. PLK1 inhibition has various effects in cancer cells, including cell cycle arrest and death. Some cancer cells are resistant to the effects of PLK1 inhibition. PLK1 inhibitors are well tolerated, but only a minority of unselected patients with NSCLC responds to this single-agent therapy. Predictive biomarkers have not yet been used to select patients likely to respond to PLK1 inhibitors, making this unknown a major gap in knowledge that addresses the Fiscal Year 2016 Lung Cancer Research Program Area of Emphasis: Understanding predictive and prognostic markers to identify responders. To address this gap, we determined sensitivity to three PLK1 inhibitors in 63 NSCLC cell lines. Following PLK1 inhibition, mesenchymal cells died and epithelial cells slowed their growth rates but survived. The induction of apoptosis (cell death) in some NSCLC cell lines using very low drug concentrations motivated us to assess sensitivity to PLK1 inhibitors by basal gene and protein expression level as well as by gene mutations. The objective of the proposed translational research award is to perform late-stage preclinical work in preparation for clinical trials using EMT as a biomarker of response to PLK1 inhibitors. Additionally, we will investigate combination therapy using immunotherapy that has also demonstrated efficacy in mesenchymal NSCLC and combinations that enhance PLK1 inhibitor-induced apoptosis in NSCLC. We will address these objectives with the following specific aims. Aim 1: To validate mesenchymal biomarkers as predictors of PLK1 inhibition-induced apoptosis (cancer cell death) in NSCLC in vivo using patient-derived xenografts (patient tumors implanted directly into mice) and an immunocompetent, orthotopic model of NSCLC (mouse with intact immune systems in which lung cancer grows in the lungs of the mice). Aim 2: Test the combination of anti-PD1 immunotherapy with PLK1 inhibition in vivo. Aim 3: To determine if FAK (a protein that increases after PLK1 inhibition in resistant cell lines) mediates PLK1-inhibitor induced apoptosis in NSCLC in vitro and in vivo. The successful completion of this project will validate PLK1 as a potential therapeutic target for mesenchymal NSCLC and provide prospective biomarkers of response to PLK1 inhibitors that could be used to select patients for future clinical trials. Immunotherapy with anti-PD1 antibodies is now standard of care for NSCLC and although responses are durable, only a minority of patients respond. Aim 2 will determine if the combination of PLK1 with PD1 inhibitors is efficacious in mesenchymal NSCLC. As both agents are in clinical use, clinical trials would be rapidly perused if warranted. Our laboratory has the resources and expertise to complete the proposed studies as well as the ability to translate our findings into clinical use in the near future. We will build on these findings with detailed mechanistic studies in future proposals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710206
Entities
People
- Faye M Johnson
Organizations
- United States Army
- University of Texas at Austin