Polyploidy: A New Breast Cancer Subtype And A Lead Compound That Targets It With High Selectivity

Polyploidy, the presence of extra chromosome sets, is a feature of many cancers. Polyploid cells have weaknesses that can be exploited for treatment–termed synthetic lethal. We identified polyploid breast cancers and a polypoid-selective lead compound. METHODS: We performed 6-chromosome FISH on 354 human breast cancers and correlated with breast cancer subtype and clinical outcomes of up to 10 years (cohort 1). To validate findings, we analyzed chromosome-17 ploidy on a second cohort of 1095 samples (cohort 2). To identify a polyploid-selective lead compound, a two-stage chemical screen was performed. First, we analyzed data from 45,342 compounds by the NCI Developmental Therapeutics Program to identify compounds selective for high ploidy cell lines. Second, we performed a secondary screen using matched diploid-tetraploid human cells. RESULTS: FISH analysis demonstrates that 10-14% of breast cancers are polyploid (≥3N). Polyploid tumors are commonly estrogen-receptor negative, but are found amongst all subtypes. Outcomes are worse for polyploid cancers than non-polyploid breast cancers in both cohorts (OS; p=0.008 cohort 1, p=0.049 cohort 2; RFS p=0.008, p=0.003). Our primary in silico screen identified potential polyploid-selective compounds. Of these, 35 were procured and tested in the secondary screen using matched diploid-tetraploid human cell lines. One compound, DPBQ, was found to have selective effects on polyploid cells. DPBQ has 3.6-fold selectivity for inhibiting proliferation of tetraploid over diploid cells. A structure-function analysis defined the key chemical motifs required for maintaining polyploid selectivity. Mechanistically, DPBQ selectively induces p53-activation and apoptosis in polyploid cells. However, other chemicals that cause p53 activation and apoptosis lack such selectivity, indicating that DPBQ operates via a unique mechanism. DISCUSSION: Polyploidy indicates an aggressive subtype of breast cancer. Polyploid cells have phenotypes distinct from normal diploid cells, suggesting an opportunity for selective therapeutics. DPBQ is one compound identified by a two-stage screen. This screen enforced the specificity of the effect for polyploid cells and also the external validity across diverse cancer cell types. Mechanistically, DPBQ selectively induces p53 activation and apoptosis in polyploid cells. It will be important do define the direct molecular target of DPBQ. CONCLUSIONS: Polyploid breast cancers represent a unique high-risk subtype of breast cancer. DPBQ is a lead compound that for selective destruction of polyploid cancers. Citation Format: Mark E. Burkard, Alka Choudhary, Robert F. Lera, Ross Fedenia, Craig Kanugh, Jennifer J. Laffin, Lauren M. Zasadil, Beth A. Weaver, Kari B. Wisinski. Polyploidy: A new breast cancer subtype and a lead compound that targets it with high selectivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2526. doi:10.1158/1538-7445.AM2014-2526