Abstract B267: Inhibition of PLK4 as a therapeutic strategy for genomically unstable cancers deficient for PTEN.

Abstract

Abstract The unique Polo-like kinase family member, PLK4, was identified as a novel therapeutic target for breast cancer through a systematic approach that integrated functional RNAi viability profiles with molecular profiling data. PLK4 is a conserved upstream regulator of centriole duplication that is aberrantly expressed in several tumor types. Dysregulation of PLK4 activity causes loss of centrosome numeral integrity, thereby promoting genomic instability, but could also enable cancer cells to tolerate its effects. A drug discovery program was initiated that resulted in the identification of CFI-400945, a first-in-class, potent and selective PLK4 small molecule inhibitor (IC50 = 2.8 nM, Ki = 0.26 nM). CFI-400945 is highly selective towards other PLK family members (PLK1, PLK2 and PLK3 IC50s >50 µM) and numerous other protein and lipid kinase classes. Consistent with PLK4 loss-of-function studies, cancer cells treated with CFI-400945 exhibit dysregulated centriole duplication, mitotic defects and cell death. Oral administration of CFI-400945 as a single agent once daily to mice bearing human cancer-derived cell line xenografts and patient-derived xenografts (PDX) results in significant inhibition of tumor growth at doses that are well-tolerated. Superior antitumor activity in vivo is observed towards PTEN-deficient tumor models compared to PTEN wild-type tumor models. Analysis of tumor xenografts from CFI-400945-treated mice demonstrated an increase in tumor cells with aberrant mitoses compared to vehicle-treated mice, and is consistent with observations from cell culture experiments. Together, these pharmacologic results support observations from functional genetic screening that inhibition of PLK4 kinase activity is lethal for PTEN-deficient cancer cells, and suggest a new mechanism-based approach for the treatment of patients whose tumors have defective PTEN. PLK4 dysregulation may represent an adaptation cancer cells have made to tolerate the effects of genomic instability induced by loss-of-function of PTEN or other mediators, such as TP53, ATM, BRCA1 and BRCA2, and thereby is a vulnerability that may be exploited for the design of cancer cell-selective therapies. The CTA to Health Canada for CFI-400945 received approval in July 2013, and an IND has been filed at the FDA, clearing the way for clinical evaluation of the molecule in the near future. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B267. Citation Format: Jacqueline M. Mason, Dan C.-c. Lin, Xin Wei, Yi Che, Yi Yao, Reza Kiarash, Graham C. Fletcher, Mark R. Bray, Guohua Pan, Tak W. Mak. Inhibition of PLK4 as a therapeutic strategy for genomically unstable cancers deficient for PTEN. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B267.