Abstract A043: Identification of a patient enrichment strategy supporting development of a potent and selective dual TTK/CLK2 inhibitor CC-671

Abstract

Abstract CC-671 is a potent and selective TTK1 (Mps1) and CLK2 inhibitor. In support of a phase I proof of concept, we used an image-based, multiplex cell assay to evaluate the antiproliferative impact of CC-671 across a broad panel of cancer cell lines representing tumors from various anatomic origins. CC-671 potently and selectively inhibited proliferation and induced apoptosis. Cell lines representing leukemia, lymphoma, colorectal cancer (CRC), head and neck (H&N), and bladder cancers were uniformly sensitive to CC-671 while the cell lines from other tumor types, such as breast and lung cancers, were differentially sensitive to CC-671. Cell cycle analysis using phospho-histone H3 (pHH3) as a mitosis biomarker suggested that CC-671 had cell line-specific mitotic effects. CC-671 accelerated mitotic exit in 120 cell lines while causing mitotic block in 37 cell lines at concentrations < 1 μM. Custom gene expression signatures correlating with sensitivity or resistance were generated. Mapping these signatures to a gene expression database of clinical tumor samples identified additional CC-671 sensitive tumor types including Wilms tumor, superficial bladder cancer, triple-negative, and luminal Btype breast cancer, and several squamous cell carcinomas (lung, esophageal, cervical, H&N). To identify a breast cancer patient selection profile, the CC-671 antiproliferative activity was assessed in a panel of 49 breast cancer cell lines. CC-671 potently inhibited the growth of breast cancer cell lines with 50% inhibitory concentrations (IC50 values) < 100 nM in 14 lines and > 10 μM in 21 lines. Triple-negative breast cancer (TNBC) cell lines were significantly more sensitive to CC-671 than non-TNBC (ER+/PR+ and/or HER2+) lines. Within TNBC, the mesenchymal (M) and basal-like 1 (BL1) subtypes were more sensitive to CC-671. In addition, TNBC lines with cancer stem cell (CSC)-like properties were also sensitive, indicating a potential role of TTK1 and CLK2 in cancer stem cells. Interestingly, mutations in several genes (phosphatidylinositol-4,5-bisphosphate 3kinase 110 kDa catalytic subunit alpha [PIK3CA], serine/threonine kinase 11 [STK11], and phosphatase and tensin homolog [PTEN]) in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway tend to associate with CC-671 TNBC sensitivity. These mutational correlates are being confirmed in additional TNBC lines. Citation Format: Shuichan Xu, Tam Tran, Tao Shi, Ning Jiang, Dan Zhu, Jennifer R. Riggs, John Boylan. Identification of a patient enrichment strategy supporting development of a potent and selective dual TTK/CLK2 inhibitor CC-671 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A043.