Abstract 3904: Overcoming resistance to HER2 inhibitors through cell based screening

Signaling from the human epidermal growth factor receptor (HER) family of proteins is dependent on a well-orchestrated series of interactions between family members to form either homo- or heterodimers. The heterodimeric complex formed by HER2 and HER3 is a particularly potent oncogenic signaling unit that can act as a driver of cancer growth and has also been shown to rescue a large number of cancers from a variety of targeted agents. The currently available therapies targeting HER2, such as Lapatinib or ado-trastuzumab emtansine, have dramatically improved patient outcomes in the clinic but preferentially target the protein in its monomeric state. Because of this, increasing the concentration of the HER2/HER3 heterodimer, either by growth factors or increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes their activity. In order to find a next generation inhibitor of the active HER2/HER3 oncogenic complex we screened 1 million small molecules against an engineered Ba/F3 cell line dependent on ligand stimulated HER2/HER3 signaling for survival. The removal of non-selective inhibitors using alternative Ba/F3 cell lines resulted in the identification of a single core scaffold hit. A medicinal chemistry campaign enabled by a co-crystal structure of a hit compound complexed to EGFR led to the development of a molecule capable of inhibiting the active state of HER2. As a result, this next generation HER2 inhibitor is capable of inhibiting growth factor stimulated HER2/HER3 heterodimers and mutationally activated forms of HER2, which are resistant to current clinical small molecule HER2 inhibitors. Citation Format: Chris J. Novotny, Sirkku Pollari, Jin H. Park, Mark A. Lemmon, Peter G. Schultz, Weijun Shen, Kevan M. Shokat. Overcoming resistance to HER2 inhibitors through cell based screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3904.