Abstract 3844: TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models

Abstract

Abstract TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is currently being investigated in Phase I and II clinical trials. SYK is expressed ubiquitously in hematopoietic cells, and abnormal function of SYK has been implicated in several types of hematopoietic malignancies, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and peripheral T-cell lymphoma (PTCL). Although there are considerable data supporting a role for SYK signaling in hematological cancers, data on the relevance of SYK in solid tumors are emerging. The literature suggests that SYK expression plays a role in the growth of breast and ovarian cancers, and the pancreatic adenocarcinoma microenvironment has been shown to be B-cell rich, giving us a basis to explore the activity of TAK-659 in these indications. Furthermore, ovarian cancer patients with recurrent disease have been shown to have an increase in pSYK at the time of relapse versus at diagnosis, suggesting a role for SYK in chemoresistance. The ability of TAK-659 to inhibit ex vivo colony formation of cells with the ability to grow anchorage independently in semi-solid medium was examined in 31 different human tumor xenografts. TAK-659 showed concentration-dependent inhibition of tumor colony growth in 5/31 tumor models tested, including gastric, breast, and ovarian cancers. Pre-clinically, TAK-659 has exhibited significant antitumor activity in a number of mouse xenograft models of solid tumors. We demonstrate here that daily oral administration of TAK-659 at 60mg/kg over 21 days leads to significant antitumor activity in primary human tumor models of gastric, pancreatic, triple negative breast (TNBC), and ovarian cancers, all of which express pSYK. Significant anti-tumor activity was also observed in the HCC70 TNBC xenograft model which does not express total SYK, demonstrating that TAK-659 may have anti-tumor effects beyond the inhibition of pSYK signaling. A decrease in myeloid derived suppressor cells was seen following TAK-659 treatment in this xenograft model, suggesting an immunomodulatory response may be driving the antitumor activity. Taken together, these data along with published information support the rationale for the investigation of TAK-659 in solid tumor cancer indications. Citation Format: Jessica J. Sappal, Matthew Theisen, Zhongmin Xiang, Stephen Tirrell, Rudy Christmas, Jie Yu, Mengkun Zhang, Karuppiah Kannan. TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models [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 3844.