Phosphoinositides conversion in the regulation of cytokinesis: PI4KA in tetraploidy induction and breast cancer progression

Phosphoinositides guide a tight spatiotemporal control over the cytosolic regulators that govern cytokinesis. Aneuploidy is a crucial hallmark of cancer progression, promoted by tumorigenesis in response to uncontrolled cell division. While aneuploidy favours the emergence of CIN, leading to cancer cell heterogeneity and resistance to therapy, it cannot increase beyond a lethal threshold for the affected cells, due to altered spindle geometry and dynamics. Our study indicates that PI4KA function is crucial in tetraploidization prevention. Specifically, PI4KA-mediated production of PI(4)P is required for correct PI3K-C2α regulation of cytokinetic abscission. Reduced levels of PI4KA in human breast cancer cells lead to rapid tetraploidization as well as CIN. We used a zebrafish model of Pi4kaa deficiency to correlate the loss of PI4KA midbody-specific function to early cell refusion. Pharmacological inhibition of PI4KA raises proliferation defects and leads to multinucleation in early cytokinesis. Interestingly, publicly available databases show that reduced PI4KA mRNA expression can be found in almost 40% of BC patients and this condition significantly correlates with both TNBC subtype and increased score of aneuploidy. In NGS xenograft mice models, PI4KA-deficiency increases tumor growth rates of human breast cancer lines. Also, PI4KA inhibition perturbs mitosis and induces binucleation of cultured TNBC lines, ultimately promoting cancer-specific vulnerabilities of the spindle assembly checkpoint related to supernumerary centrosome clustering. The resulting increased and selective sensitivity of TNBC lines to SAC inhibition suggests that a combinatorial approach targeting both PI4KA and SAC, at very low doses, induces aberrant multipolar spindles, excessive chromosome mis-segregation and lethal aneuploidy.