Identification of head and neck cancers (SCCHN) that may respond to dual inhibition of EGFR and HER3 signaling

• Published in: Journal of clinical oncology Vol. 30; no. 15_suppl; p. 5575
• Main Authors: Shames, David S., Stern, Howard, Walter, Kim, Jiang, Brittany, Fu, Ling, Do, An, Raja, Rajiv, Wilson, Tim, Settleman, Jeff, Sliwkowski, Mark X., Pirzkall, Andrea, Amler, Lukas C.
• Format: Journal Article
• Language: English
• Published: 20.05.2012
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2012.30.15_suppl.5575

Abstract only 5575 Background: Oncogenic signaling through the epidermal growth factor receptor family is one of the most frequent alterations found in human epithelial cancers. These receptor tyrosine kinases mediate their effects via high-level co-expression and homo- and heterodimerization events that drive tumor growth, metastasis, and survival. Extensive preclinical studies suggested that some cell lines depend on oncogenic autocrine signaling through HER3 (Wilson et al.). This phenotype was particularly prominent in cell lines derived from SCCHN and was strongly correlated with high HRG expression. Interestingly, two patients with SCCHN tumors that expressed high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, a dual-action human IgG1 antibody that blocks ligand binding to EGFR and HER3 (Schaefer et al.) had partial responses. To further explore the hypothesis that high-level HRG expression defines a sub-population of SCCHN that may be sensitive to agents targeting HER3, and to identify other potential target indications for the development of MEHD7954A, we evaluated the expression of HRG in large cohorts of multiple solid tumor indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR in 648 formalin-fixed paraffin embedded primary tumor samples from patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast cancer. Results: SCCHN-derived tumor samples had the highest levels of HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern that is clearly distinct when compared to other tumor types. These data suggest that high HRG levels and potentially HER3-dependent autocrine signaling occur more frequently in SCCHN than in other tumors. Further we investigated whether overexpression of HRG in SCCHN correlated with stage and disease outcome. Updated results from these extended studies will be presented. Conclusions: SCCHN tumors exhibit bimodal expression of HRG, suggesting that HRG expression levels may be useful in identifying a subset of patients most likely to benefit from inhibition of HER3 activity. Antitumor activity in such patients has been observed in a phase I study of MEHD7954A (abstract #95245).