Dissection of molecular triggers for genomic instability and cell death in cells treated with Chk1 inhibitors.

CALZETTA, NL., GONZALEZ BESTEIRO M., GOTTIFREDI V.

Congreso; XVII Congreso Latinoamericano de Genética, (ALAG/2019).; 2019

Checkpoint kinase 1 inhibitors are been tested in the clinic because they trigger cancer cell death as a consequence of hampering damaged DNA replication. One negative aspect of Chk1 inhibition is the accumulation of chromosome instability, which has been associated with tumor adaptation to the treatment. It is currently accepted that cell death and chromosomal instability are tightly linked because they are both triggered by suboptimal DNA replication in the absence of checkpoint signals. Here we show that bulk DNA replication defects can be recovered after Chk1 inhibition in a manner that correlates with full rescue of cell survival but no elimination of chromosome instability. Conversely, we will also show molecular events that control chromosome instability without affecting the extent of cell death triggered by Chk1 inhibition. Such information may be of use when attempting to improve treatments involving Chk1 inhibitors. Our work may also prompt the search of molecular signals that specifically control genomic instability but not cell deathwhen using other treatments disrupting key DNA damage response pathways which may have or will be transferred to the clinic.