In Vivo Acquired Resistance To An Emibetuzumab Analogue In Met-Amplified Gastric Xenografts Can Be Overcome By A Met-Targeting Antibody Mixture Or Pik3ca/Akt/Mtor Inhibition

Aberrant over-activation of MET receptor tyrosine kinase is involved in driving malignancies such as gastric and non-small cell lung cancer (NSCLC), and in the development of resistance to EGFR-targeting therapeutics. This has led to the development of several MET-targeting agents in the form of tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), many of which are in clinical development. However, resistance to MET-targeted agents is an emerging problem. This study aims to understand mechanisms underlying resistance development to an analogue of emibetuzumab, a mAb targeting MET. Upon long term in vivo treatment, emibetuzumab-resistant tumors and cell lines were generated, isolated, and characterized to investigate their acquired resistance mechanisms. Extensive reverse phase protein array and network analysis were used to characterize the proteomic profiles of three resistant cell lines, revealing three distinct resistance profiles, one involving activation of the PI3Kinase/AKT/mTOR pathway. We further show, how these resistance mechanisms can be overcome by treatment with other targeting therapeutics both in vitro and in vivo. Two of the models demonstrated in vivo sensitivity to Sym015, a novel mixture of two mAbs targeting non-overlapping epitopes of MET, partly due to ADCC, indicating that Sym015 can overcome acquired resistance to emibetuzumab. The third model demonstrated a marked increase in PI3Kinase/AKT/mTOR pathway activation. This activation translated into induced cancer cell and tumor growth, which could be inhibited by agents targeting PI3Kinase, AKT, or mTOR. This study thus points to treatment of patients with acquired resistance to single targeting MET mAbs with PI3Kinase/AKT/mTOR-targeting agents or a MET-targeting antibody mixture such as Sym015. Citation Format: Sofie Ellebaek Pollmann, Emanuel Frank Petricoin, Valerie Calvert, Shruti Rao, Simina Boca, Subha Madhavan, Ivan David Horak, Andreas Kjaer, Michael Kragh, Thomas Tuxen Poulsen. In vivo acquired resistance to an emibetuzumab analogue in MET-amplified gastric xenografts can be overcome by a MET-targeting antibody mixture or PIK3CA/AKT/mTOR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3158. doi:10.1158/1538-7445.AM2017-3158