IMPROVING THE QUALITY OF CELL KILLING BY CHK1 INHIBITORS

CAIMI, LILEN; CALZETTA, NICOLAS; GOTTIFREDI, VANESA

Mendoza

Congreso; LVIII Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research; 2022

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

Due to their fast proliferation, tumor cells replicate their genome more frequently than normal cells. Such a difference is exploited by many of the currently approved chemotherapy regimens that cause replication stress-mediated cancer cell killing. The main drawback of this strategy is the accumulation of chromosome instability (CIN) in the fraction of cancer cells that survive the treatment. The accumulation of CIN is a potential cause of treatment failure as there are no current tools to prevent it, and it can introduce mutations that promote the acquisition of resistance to the treatment. One novel approach under clinical investigation is using checkpoint kinase 1 inhibitors, Chk1i. As with other approved therapies, Chk1i causes replication stress, CIN and cell death (CD) in cancer cells. Here, we present data showing that the inhibition of PLK1, a master regulator of mitosis progression, prevents CIN without affecting the CD caused by Chk1i. We have previously shown that, whereas Chk1i-triggered CD is associated with acute replication stress in S phase, CIN accumulates in cells that finalize S phase and fail to duplicate under-replicated DNA (UR- DNA) in M phase fully. These results demonstrate that CD and CIN after Chk1i are dissectible at the molecular level, suggesting that M-phase triggered CIN could be reduced without impairing S-phase associated CD. While more work is required to understand the molecular basis of the counteracting effect of PLK1 inhibition on CIN induction, these results provide a proof of concept for the design of novel anti-cancer strategies aimed at inducing a CIN-free CD of cancer cells.