[CHEK1 expression and inhibitors in TP53 mutant cancer]. / A checkpoint kinase 1 expressziója és gátlása TP53-mutációt hordozó rosszindulatú daganatokban.

ABSTRACT

The most frequently mutated gene in human tumors is TP53 and its mutation significantly deteriorates patients' survival. However, to date no targeted therapy is established for TP53 mutated tumors. Here, our aim was to identify druggable kinases with higher expression in TP53 mutated tumors, as well as relate these to altered prognosis. We also aimed to validate a target gene in TP53 wild type and mutant isogenic cell lines using a specific kinase inhibitor. Gene expression and mutation data were collected from 994 lung tumor samples. Samples were separated based on TP53 mutation status, and differential gene expression was compared using Mann-Whitney test between patient cohorts. Prognostic value of identified genes was validated in an array-based lung cancer dataset (n=1926). Survival analysis was performed using Cox proportional hazards regression and Kaplan-Meier survival plots. Effect of TP53 mutations on CHEK1 expression was validated in the A549 isogenic lung cancer cell line. The cell line was also treated using Chk1 protein specific kinase inhibitor to monitor cell functions. Expression of CHEK1 was elevated significantly among targetable kinases and higher expression of CHEK1 related to worse prognosis. Our results confirm the higher expression of CHEK1 kinase associated to TP53 mutations and to shorter survival.