The Faye Johnson Laboratory currently has three main projects:
We recently discovered that head and neck squamous cell carcinoma (HNSCC) tumors harboring NOTCH1 mutations were significantly more sensitive to seven different drugs targeting the PI3K/mTOR pathway than HNSCC cell lines with wild-type NOTCH1 receptors. Unlike HNSCC tumors with PIK3CA mutations which exhibited only growth arrest after treatment with PI3K/mTOR inhibitors, tumor lines harboring NOTCH1 mutation also underwent cell death. Goals of this project are to: 1) Determine the efficacy of PI3K/mTOR pathway inhibition in HNSCC patients with tumors that harbor inactivating NOTCH1 mutations through a clinical trial; 2) Elucidate the molecular mechanism underlying PI3K/mTOR dependency and sensitivity to drugs targeting this pathway in HNSCC tumors with NOTCH1 mutations; and 3) Identify molecular therapeutic targets that work in combination with PI3K/mTOR inhibitors to prevent resistance and maximize killing of HNSCC tumors harboring NOTCH1 mutations. This research proposal represents one of the first targeted therapies to be based upon newly identified genomic alterations in HNSCC and to target a tumor suppressor in this cancer type.
We previously demonstrated that mesenchymal non-small cell lung cancer (NSCLC) was sensitive to polo-like kinase 1 (Plk1) inhibitors, but the mechanisms of resistance to Plk1 inhibitors in epithelial NSCLC remains unknown. We used isogenic pairs of epithelial and mesenchymal NSCLC cell lines to measure changes in the expression of 301 proteins after Plk1 inhibition. We observed differential regulation of the cMet/FAK/Src 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 inhibitor–induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor–induced 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 β1 integrin. This research defines a heretofore unknown mechanism of ligand-independent activation of cMet downstream of Plk1, as well as an effective combination therapy.
A recently completed screen of 1122 unique drugs in HPV+ cancer cell lines identified clinically-relevant Aurora kinase inhibitors as effective drugs in these cells. Integrated analysis of genomics, proteomics, gene expression, and drug sensitivity has demonstrated that KMT2D (MLL2) mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora kinase inhibitor–induced apoptosis. Goals of this study are to define the underlying mechanisms of sensitivity in KMT2D mutant HNSCC.