The Faye Johnson laboratory integrates laboratory and clinical work to define the biological and molecular effects of the modulation of signal transduction pathways in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). We have identified novel mechanisms of sensitivity and resistance to inhibitors of Aurora kinase, the phosphoinositide 3-kinase (PI3K) pathway, polo-like kinase 1 (PLK1), Src, and STAT3. We have demonstrated the ability to translate our laboratory work to the clinic with several clinical trials of PI3K, Aurora, c-Src inhibitors. We were the first study to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC to any class of drugs leading to the initiation of a clinical trial testing a PI3K/mammalian target of rapamycin (mTOR) inhibitor in NOTCH1-mutant HNSCC (NCT03740100). Our further mechanistic work defined a novel pathway in which Aurora B regulates total AKT levels that subsequently regulate PDK1 selectively in NOTCH1 mutant HNSCC, where these proteins mediate survival in response to PI3K inhibition. Recently, we have discovered that inhibition of Aurora kinase in human papilloma virus (HPV)-driven cancers leads to apoptosis and immunogenic cell death. These findings are the basis for my investigator-initiated clinical trial (NCT04555837) combining the inhibition of Aurora A (alisertib) and PD1 (pembrolizumab). We defined a novel pathway in which HPV-positive cancer cells maintain a balance of the mitotic checkpoint gene MAD2L1 and its regulator TRIP13 to allow mitotic exit and survival in the absence of retinoblastoma (RB) protein expression.