The Faye Johnson Laboratory currently has three main projects:
We study the role of polo-like kinase 1 (PLK1) in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). We recently discovered that mesenchymal NSCLC cell lines were more sensitive to PLK1 inhibitors than epithelial lines in vitro and in vivo. PLK1 inhibitors induce apoptosis and DNA damage in mesenchymal NSCLC cell lines. Moreover, induction of the epithelial to mesenchymal transition (EMT) increases sensitivity of NSCLC cells to PLK1-induced apoptosis. We are investigating the roles of EMT and DNA repair in the response to PLK1 inhibitors. In parallel, we are also studying PLK1 inhibitors in combination with chemotherapeutic agents and DNA repair protein inhibitors in NSCLC. This project is led by post-doctoral fellow Ratnakar Singh, Ph.D.
The goal of our second project is to identify new therapies for human papillomavirus (HPV)- associated cancers that include HNSCC as well as cervical, anal, and penile squamous cancers. Approaches include: conducting a high throughput drug screen with 1200 compounds on HPV-driven cancer cell lines to identify drugs that exhibit differential sensitivity based on HPV-status; silencing the expression of viral oncogenes (E6, E7) by establishing HPV-driven cell lines that contain stable, inducible shRNAs for HPV16 E6 and E7; and performing shRNA screens using a novel custom shRNA library of genes most frequently altered by HPV integration to determine their role in cancer progression. This project is led by post-doctoral fellow Nene Kalu, Ph.D.
The primary focus of our third project is the identification and characterization of predictive biomarkers of sensitivity/resistance to PI3K/mTOR pathway inhibition in HSCCC. This project takes advantage of a cell line database that includes whole exome sequencing, RNA Seq expression, drug sensitivity and protein expression data (reverse phase protein array) on about 70 HNSCC cell lines. In collaboration with our colleagues in Bioinformatics, we have integrated drug sensitivity with molecular profiles of HNSCC cell lines and discovered that HNSCC cell lines bearing NOTCH1 mutations are exquisitely sensitive to PI3K/mTOR pathway inhibition. Identification of the involved pathways is both mechanistically important and will increase the translational potential of PI3K/mTOR inhibitors in the clinic. We are currently studying the cross talk between the PI3K/mTOR and NOTCH1 pathways. This project is led by post-doctoral fellow Vaishnavi Sambandam, Ph.D.
Johnson also co-leads a drug screening effort in collaboration with Hai Tran, Pharm.D., that is funded by the Lung Moonshot. The cell line database that includes whole exome sequencing, RNA Seq expression data, drug sensitivity (1200 drugs) and protein expression data (reverse phase protein array) on about 100 NSCLC cell lines.