HER3-biased Sec61 modulators for treatment of cancers

Tobacco usage is the largest risk factor for head and neck squamous cell carcinomas (HNSCCs). Smokers diagnosed with HNSCC exhibit reduced overall survival relative to non-smokers. Moreover, HNSCC patients who are current tobacco users are at a higher risk of disease recurrence compared to patients that have never used tobacco. Several studies indicate that the cell-surface receptor HER3, a member of the human epidermal growth factor receptor family, plays an essential role in HNSCC. HER3 expression is correlated with worse overall survival in HNSCC patients. HER3 has also been linked to other types of cancer such as breast, ovarian, colon, and EGFR-driven lung cancers.

Therapeutic antibodies that target the extracellular portion of HER3 have produced disappointing results in clinical trials, possibly due to the resistance caused by the growth factor-independent HER3 signaling. Thus, novel therapeutic approaches are needed to completely block HER3 functions. We believe that drugs that can eliminate HER3 protein expression will show superior efficacy compared to function-blocking antibodies. Recently, we have developed novel small molecules that inhibit HER3 biosynthesis, resulting in the elimination of HER3 from cancer cells. In this project, I propose to develop novel chemistry approaches to identify HER3 modulators with greater potency and selectivity. These compounds will be tested in preclinical models of HNSCC.