Abstract Abstract #3155 Background: The HER (ErbB) receptor family plays a major role in the proliferation of tumor cells. Overexpression of these receptors occurs in breast and a variety of cancers and correlates with poor prognosis. We have identified TAK-285, a potent, selective and orally bioavailable small molecule inhibitor of HER kinases. TAK-285, which is currently in clinical trials for the treatment of solid tumors, inhibits EGFR (also known as ErbB1 or HER1) and HER2 (also known as ErbB2) and exerts clear anti-proliferative activity in in vitro and in vivo tumor models. Here, we elucidated the determinants of TAK-285 anti-tumor activity in vitro in a panel of human cancer cell lines.
 Methods: Cell growth inhibition assay was performed using sulforodamine B staining method or CellTiter-GloTM assay (Promega). Candidate gene expressions were measured by quantitative PCR. Associations between the IC50 values and the candidate gene expressions were statistically analysed.
 Results: TAK-285 exerted anti-proliferative effects in all of cell lines tested in a dose dependent manner but the effects ranged widely (IC50: 0.011-over 10 µmol/L). Statistical analysis showed an inverse correlation between sensitivity to TAK-285 (IC50 values) and HER2 or HER3 (also known as ErbB3) gene expression. PTEN or IGF-1R gene expression, reported to be involved in trastuzumab resistance, was not correlated with TAK-285 sensitivity. Immunoblot analysis revealed that HER2 and HER3 are coexpressed in most TAK-285 sensitive cells and TAK-285 inhibited phosphorylation of HER3. Because HER3 does not possess kinase activity, this suggests that HER3 is trans-phosphorylated by HER2. Knockdown of HER3 using siRNA inhibited tumor cell growth in TAK-285 sensitive cells but not in TAK-285 insensitive cells.
 Conclusion: These results suggest that HER2 and HER3 mainly regulate tumor cell growth in TAK-285 sensitive cells and could be used as a molecular marker to select patients who are likely to respond to TAK-285. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3155.