Methods to monitor the relevance of M phase in the synthetic lethal potency of Polo-like Kinase inhibitors

SIRI, SEBASTIÁN OMAR; GOTTIFREDI, VANESA; OKRAINE VERONICA YIOVANA

Buenos Aires

Simposio; Buenos Aires Breast Cancer Symposium BA-BCS2021; 2021

Homologous recombination (HR) deficiency due toloss of BRCA function in cells leads to a propensity to thegenesis of different types of cancer. Conversely, such HRdeficiency is exploited to cause synthetic lethality (SL) ortumor-specific cell death in BRCA-deficient cancers. Sucha synthetic lethality can be achieved by using drugs suchas PARP inhibitors (PARPi) that prompt the accumulationof substrates for HR, e.g., DNA double-strand breaks(DSBs), which cannot be repaired in HR deficient cells. Thetrigger for SL in BRCA deficient cells treated with PARPi isintimately associated with acute DNA replication stress. Incontrast, we have recently reported that BRCA1-deficientcells can be killed in a manner independent from such an Sphase-associated stress. We found that inhibition of PLK1,an M-phase master kinase, causes SL in BRCA1 deficientmodels in a manner that does not augment parametersof DNA replication stress. Instead, BRCA1-deficient cellstreated with PLK1i aggregate into multinucleated structuresthat suggest M phase’s role in the SL triggered by PLKi. Toget insight into such a DNA replication stress-independentSL mechanism, we will systematically monitor chromosomesegregation, and other M phase parameters (multipolarmitoses, chromosome bridges, and lagging chromosomesresolution) will be discussed in depth during the presentation of results.