Abstract 5331: Targeted protein degradation for the treatment of TRK fusion-driven cancers

Abstract

Abstract Small molecule-mediated targeted protein degradation offers a systemic approach to deplete disease-causing proteins. The tropomyosin receptor kinase (TRK) family kinases are receptors for neurotrophic factors and primarily function in the central nervous system. As results of chromosomal rearrangement events, TRK kinases are re-expressed as fusion proteins and implicated in a wide diversity of human malignancies. These fusion proteins universally retain the kinase domain and function as key oncodrivers. Two TRK kinase inhibitors, entrectinib and larotrectinib, have been approved to treat TRK fusion-expressing cancers with compelling clinical evidence, highlighting the significance of TRK fusion kinases as oncology targets. In the current study, we report the development of selective TRK degraders. Lead compounds induced rapid degradation of different TRK fusion variants identified in patients at subnanomolar concentrations. Degradation of the fusion kinases significantly compromised TRK-dependent cancer cell growth with low nanomolar IC50. The lead compound exhibited approximately 16% oral bioavailability in mouse and effectively controlled TRK-driven xenograft tumor growth. Pharmacodynamic analysis demonstrated sustained degradation of the TRK fusion in xenograft tumors. Collectively, these findings provide the framework to develop a novel approach that modulates oncogenic TRK fusion kinases for cancer treatment. Citation Format: Xiaoran Han, Liqun Chen, Chengwei Zhang, Bingyang Jiao, Yanke Chen, Jing Liu, Michael Plewe, Jialiang Wang. Targeted protein degradation for the treatment of TRK fusion-driven cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5331.