7IN - Targeting Cancer Aneuploidy: Light at the End of the Tunnel?

Abstract

ABSTRACT For the last three decades, the “Oncogene Revolution” prompted investigators to develop agents against oncogenes, with the goal of blocking cell growth and metastasis. It is now clear that the cancer cell genome is too varied oncogenes too numerous for this strategy to work effectively for most tumors. One new approach takes advantage of an alteration shared by many advanced cancer cells but not found in normal cells: aneuploidy. The generation of an abnormal chromosome number is driven by chromosomal instability. By supplying extra copies of genes and/or regulators, aneuploidy creates a genetic imbalance that alters a cell's behavior and its ability to complete mitosis, a situation that should kill the cell. However, most aneuploid tumor cells can deregulate specific subsets of genes so as to retain their abnormal chromosomal integrity during cell division. This maintenance of the aneuploid state permits the cancer cell to continue its altered behavior, contributing to further genomic instability and accelerating tumor progression. We hypothesized that disruption of this deviant process might be exploited to terminate the mitosis of aneuploid cells. By using multi-dimensional datasets for human breast cancer and focussing on cancer cell aneuploidy, we identified polo-like kinase-4 (PLK4), an enzyme critical for aneuploidy maintenance, as a promising therapeutic target. We conducted a drug discovery program that culminated in the isolation of CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects and cell death. Importantly, CFI-400945 has significant antitumor activity as a single agent in preclinical tumor models. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in significant inhibition of tumor growth at doses that are well-tolerated. Among these cancer xenografts, CFI-400945 exhibits increased antitumor activity against PTEN-deficient xenografts compared to PTEN wild-type xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors exhibiting aneuploidy, and particularly for malignancies deficient in PTEN. Disclosure: The author has declared no conflicts of interest.