Abstract ES2-1: Mechanisms of HER2 signaling, targeting, and resistance

The amplification and overexpression of the oncogene HER2 underlies the pathogenesis of a distinct subset of breast cancers. Our understanding of this oncogene and its role in cancer biology has evolved tremendously since its identification in the 1980s. A wide spectrum of experimental models including mouse genetic models, reversible genetic models, and shRNA knockdown models confirm that overactivity of this oncogenes underlies the pathogenesis of breast cancers and continues to be its major driving force throughout the disease course. A principal consequence of HER2 overexpression is constitutive signaling in the absence of ligand stimulation, with consequent activation of a number of downstream signaling cascades including the Ras-MAPK and PI3K-Akt pathways, and many transcriptionally induced genes with diverse functions. Genes recognized to be important in mediating the HER2-driven tumorigenic phenotype include ETS, PTPN1, COX2, FASN, and CXCR4 and each of these collateral targets is being pursued for drug development. The past decade has brought about considerable insights into the physiological mode of signal generation by HER2, which occurs through heterodimerization with its ligand-inducible partners EGFR, HER3, or HER4. But we know much less about how constitutive signaling is generated in the pathologic state of HER2 overexpression and this remains a principal barrier in the field. HER2 has multiple attributes that make it suitable for drug development through a variety of targeting mechanisms. Its kinase-dependent signaling activity make it suitable for the tyrosine kinase inhibitor (TKI) class of drugs. Its dimerization-dependent mode of signaling have led to the pursuit of dimerization-disrupting drugs. Its massive expression at the cell surface make it suitable for immunotherapy approaches as well as immunodelivery approaches. While this diverse mechanistic landscape has created fertile ground for drug development, it has also created signficant complexity, difficulty, and misconception in understanding their modes of action , mechanisms of resistance, and has undermined the development of clinically useful predictive biomarkers. This accounts for the failure of signaling-based biomarkers to predict clinical trastuzumab resistance and has shifted the focus on markers of immunologic activity. Some agents may have more than one mechanism of action, further complicating the study of drug resistance and biomarker development. There is strong evidence implicating HER3 as an obligate partner of HER2 in tumorigenesis. HER3 functions both upstream and downstream of HER2 and the HER2-HER3 complex appears to be the functionally relevant tumorigenic driver of HER2-amplified cancers. Importantly, HER3 comprises a highly dynamic component of the HER2-HER3 signaling complex with a robust ability to increase signaling from the complex when HER2 activity is targeted by drugs. This places this tumor driver beyond the therapeutic index of all HER2 targeting drugs developed to date accounting for the limited monotherapy activities seen with such drugs. The development of highly effective agents awaits better functional characterization of the HER2-HER3 tumor driver and development of drugs that can more potently inactivate it, and many such lines of investigation are underway. Citation Format: Mark M. Moasser. Mechanisms of HER2 signaling, targeting, and resistance [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES2-1.