TRK receptor tyrosine kinases are expressed as fusion proteins encoded by various fusion genes across a wide variety of cancer types, including lung and colorectal cancer. These fusion proteins have… Click to show full abstract
TRK receptor tyrosine kinases are expressed as fusion proteins encoded by various fusion genes across a wide variety of cancer types, including lung and colorectal cancer. These fusion proteins have potent oncogenic activity and are thought to be an attractive therapeutic target. In a kinase inhibitor screening we identified CH7057288, a potent and selective TRK inhibitor belonging to a novel chemical class. Our inhibitor showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. In subcutaneously implanted xenograft models of TRK fusion-positive cells, strong tumor growth inhibition was observed. Furthermore, CH7057288 induced regression of intracranial tumors and greatly improved event-free survival in an intracranial implantation model mimicking brain metastasis. Recently, resistant mutations in TRK have been reported in patients showing disease progression after treatment with a TRK inhibitor under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against some of the resistant mutants as it did to wild-type TRK. In summary, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer. Citation Format: Hiroshi Tanaka, Hitoshi Sase, Toshiyuki Tsukaguchi, Hiromi Tanimura, Masami Hasegawa, Kiyoshi Hasegawa, Yoshiyuki Ono, Nobuhiro Oikawa, Hiroshi Sakamoto, Toshiyuki Mio. Potent and selective TRK inhibitor CH7057288 [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 4179. doi:10.1158/1538-7445.AM2017-4179
               
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