Abstract LB-123: Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers

Abstract

Abstract Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically available inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. To identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance, we examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Then, acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea (ENU) mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. After identifying the resistance mechanisms, we performed drug screening with small-molecular inhibitors to overcome the resistance. As the results, we identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R. As a result of drug screening, we found that cabozantinib and a few TKIs effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or LOXO101. Furthermore, cabozantinib with an insulin growth factor receptor type 1 (IGF1R) inhibitor such as OSI906 could overcome bypass pathway-mediated resistance. Thus, in this study, we developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement. In addition, we found drugs and a combination therapy to overcome the identified resistance to NTRK1-TKI. Citation Format: Ryohei Katayama, Miho J. Fuse, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita. Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers [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 LB-123. doi:10.1158/1538-7445.AM2017-LB-123