414 The Anti-tumor Activity of the ERBB3 Inhibitory Antibody AV-203 in Patient Derived Tumor Explant Models

Abstract

overexpression or shRNA. Further biochemical analysis demonstrated that unlike doxorubicin, which causes DNA damage mediated phosphorylation and stabilization of p53 and phosphorylation of H2AX, CLTX1 is a potent HdmX-specific inhibitor capable of rapidly stabilizing p53 in a DNA damage independent manner. An in vitro ELISA using recombinant p53, HdmX or Hdm2 demonstrated that CLTX1 disrupted HdmX-p53, but not Hdm2– p53 interactions. Moreover, while CLTX1 exhibits some anti-cancer activity alone when used to treat wild-type p53 expressing cell lines, particularly those that do not overexpress Hdm2, we have observed that the combined inhibition of HdmX (with CLTX1) and Hdm2 (with Nutlin 3) synergize to induce apoptosis. Overall, CLTX1 is a promising new anti-cancer agent that is capable of targeting cancer cells through the induction of p53 in a non-genotoxic manner.