LAUSR

Structural rearrangements that activate receptor kinases account for an ever-increasing pool of druggable targets in lung adenocarcinoma patients. Among these tumors RET kinase fusions and MET alterations represent two genetically distinct groups that share a common lack of clinically effective strategies. While RET rearranged tumors show a limited susceptibility to currently available RET inhibitors, MET rearranged tumors have not been yet fully appreciated as a relevant group that may benefit from treatment with MET targeted drugs. Using systematic molecular profiling of genetically engineered RET rearranged in vitro and models and patient-derived in vivo models we identified the type II kinase inhibitors ponatinib and AD80 as the most potent drugs. While both inhibitors are effective against gatekeeper mutant RET we identified a novel resistance mutation RETI788N that triggers a selective resistance against AD80 and other RET inhibitors but retains susceptibility to ponatinib. Furthermore, we studied the clinical and preclinical activity of MET targeted drugs. We specifically characterized genomic rearrangements of KIF5B-MET and STARD3NL-MET in cellular models that were found in two distinct LADC. In parallel we identified and characterized a MET kinase domain duplication that developed in an EML4-ALK rearranged positive tumor as a resistance mechanism to ceritinib. All three patients showed a partial response to crizotinib that effectively inhibits MET and ALK in these tumors. Thus, our molecular characterization of drug-target engagement in genetically defined models may further enhance the clinical efficacy of kinase inhibitors in lung tumors driven by rare oncogenic kinase alterations. Citation Format: Dennis Plenker, Carina Lorenz, Miriam Bertrand, Richard Riedel, Joop de Langen, Johannes Bragelmann, Reinhard Buttner, Jurgen Wolf, Roman K. Thomas, Johannes Heuckmann, Martin L. Sos. Targeting structural RET and MET kinase alterations in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1920.