Abstract A232: In vitro and in vivo activity of NMS-E628 against ALK mutations resistant to Xalkori.

摘要: The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase with recognized role in the pathogenesis of different tumors. There strong preclinical evidence that inhibition ALK activity results anti-tumor efficacy and approval inihibitor Xalkori (crizotinib) for treatment NSCLC patients bearing positive tumor represents most recent success targeted therapy. Nevertheless, clinical data show after initial response to Xalkori, experience relapse, mechanisms which are still under study, but at least some cases appear due emergence mutations confer resistance drug. Thus, development next-generation inihibitors, able overcome ALK-dependent needed. We have previously presented identification NMS-E628, potent selective small-molecule inhibitor activity. compound displays several models dependent tumors oral administration, complete durable regression observed treated animals. NMS-E628 passes blood brain barrier all species tested was found effectively control growth intracranial Being structurally distinct from might be domain by affecting binding. To test this hypothesis, on WT two mutants identified Xalkori-relapsed patients, L1196M C1156Y, investigated using approaches. Ki determination revealed biochemical level, ca. 7–8 fold more than both C1156Y. In Ba/F3 cells made upon mutated forms, superior inhibiting proliferation C1156Y ALK-driven vitro. Mechanism action studies confirmed drugs, better downmodulate phosphorylation, having similar potency wt forms. assess antitumor vivo, xenografts driven were generated. As expected vitro results, showed poor when 100 200 mg/kg, while retains significant mutant models. Taken together, these support idea represent valid therapeutic opportunity acquired specific mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings AACR-NCI-EORTC International Conference: Molecular Targets Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Ther 2011;10(11 Suppl):Abstract nr A232.