All roads lead to mitosis: A common requirement for DNA replication stress-dependent and -independent killing of BRCA-deficient cells.

Abstract

The deficiency in breast cancer associated proteins 1 and 2 (BRCA1 and 2) causes an early and more frequent onset of tumor genesis and progression. Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively toxic towards BRCA1 and 2-deficient tumors, sparing the healthy cells from patients from side effects. In BRCA1 and 2 deficient tumors, PARPi-mediated cell death is characterized by the augmentation of replication stress (RS) and chromosome instability (CIN) including micronuclei (MN) accumulation, a source of swift genomic rearrangements. PARPi also cause resistance to treatments which indicates the need of treatment alternatives. In this review, we discuss potential options that, similarly to PARPi, selectively kill BRCA1 and/or 2 deficient tumors. Remarkably, while many of those alternatives also upregulate MN and other CIN variables, others cause a RS-independent and MN-independent cell killing. This is the case of the inhibitors of Rho-kinase (ROCK) and, potentially, mitotic kinase Polo like kinase 1 (PLK1). Such a mode of cell killing could be advantageous if attempting to either prevent or postpone the rise of resistance clones in the tumor population that survives the treatment.