Polyploidy in Cancer: Causal Mechanisms, Cancer-Specific Consequences, and Emerging Treatments

Abstract

Drug resistance is the major determinant for metastatic disease and fatalities, across all cancers. Depending on the tissue of origin and the therapeutic course, a variety of biological mechanisms can support and sustain drug resistance. Although genetic mutations and gene silencing through epigenetic mechanisms are major culprits in targeted therapy, drug efflux and polyploidization are more global mechanisms that prevail in a broad range of pathologies, in response to a variety of treatments. There is an unmet need to identify patients at risk for polyploidy, understand the mechanisms underlying polyploidization, and to develop strategies to predict, limit, and reverse polyploidy thus enhancing efficacy of standard-of-care therapy that improve better outcomes. This literature review provides an overview of polyploidy in cancer and offers perspective on patient monitoring and actionable therapy.

Figure 1.. Genotoxic Stress induced polyploidy as a source of poor outcomes.

Stressors, such as radiation, chemotherapy, and hypoxia, lead to perturbations of the cell cycle. In the Growth 1 (G1) of the cell cycle phase, cells accomplish most of their growth, increasing in size and multiplying organelles. This is followed by a step of full genome replication, or DNA Synthesis (S) phase. Further growth and maturation occur in G2, as the cell prepares to divide in mitosis (M) phase, to distribute DNA and organelles equally into two daughter cells. These cell cycle perturbations cause polyploidy through endocycling, endomitosis, or cytokinesis failure forming mononucleated or multinucleated polyploid cells. Polyploid cells exhibit drug resistance, metastasis, and tumor growth after stressors are removed.

Figure 2.

Cell cycle targets of known polyploidy inducing drugs.