Characterization of AZD8931, a potent reversible small molecule inhibitor against epidermal growth factor receptor (EGFR), erythroblastic leukemia viral oncogene homolog 2 (HER2) and 3 (HER3) with a unique and balanced pharmacological profile

11072 Background: Successful combined pharmacological inhibition of EGFR, HER2, and HER3 signaling is currently under investigation in the clinic. HERs (erbB receptors including EGFR, erbB2, erbB3, erbB4) undergo various types of alteration and in many cancers HER ligands are produced either by the tumor cells themselves or surrounding stromal cells. These mechanisms of receptor activation all lead to constitutive proliferative and/or survival signaling driven by homo- and/or heterodimerization of the HER family. Characterization of a novel tyrosine kinase inhibitor with a potent and balanced profile against EGFR, HER2 (erbB2), and HER3 (erbB3) has been carried out. Methods: A range of assays has been developed to assess the detailed pharmacology of AZD8931 and understand how the profile of AZD8931 compares with other HER family inhibitors, such as gefitinib and lapatinib. These assays have provided unique insights into the pharmacology of these drugs that result from the varying levels of HER and their associated ligands. Results: Across a number of cell systems, AZD8931 has been shown to be a potent inhibitor of tumor cell growth. This effect is through the ability of AZD8931 to inhibit potently the phosphorylation of EGFR (0.004 μM; 95% CIR: 1.377), HER2 (0.003 μM; 95% CIR: 1.817) and HER3 (0.004 μM; 95% CIR: 1.890) in a balanced manner. Furthermore, when compared to control AZD8931 has significant and dramatic effects on the downstream signaling pathways (pAKT [p=0.002] & pMAK [NS]), apoptotic (M30 [p=0.004]), and proliferative (Ki67 [p<0.0005]) endpoints. The novel agent AZD8931 displays a distinct pharmacological profile compared to both gefitinib and lapatinib. Conclusions: Based on our data as well as published literature, the combined pharmacological inhibition of EGFR, HER2, and HER3 signaling has not yet been tested in the clinic. AZD8931 offers an agent to test the hypothesis that combined inhibition of HER signaling could provide additional clinical benefit in cancer, particularly in the majority of solid tumors that do not overexpress HER2. [Table: see text]