Selective impact of PARP-inhibition in KRAS-mutated intrahepatic cholangiocarcinomas is mediated by CHK1 kinase

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with increasing incidence over recent years. Due to complexity of iCCA pathogenesis and pronounced genetic heterogeneity treatment options are limited. Activating KRAS mutations are among the most abundant genetic alterations in iCCA and are associated with early recurrence, poor response to chemotherapy, and reduced overall survival, highlighting the need for novel therapeutic approaches. Poly(ADP-ribose)polymerase-1 (PARP-1) is frequently observed to be upregulated in iCCA. Evidence indicate potential therapeutic relevance for PARP-1 inhibition in iCCA that preferentially affects KRAS-mutated cancers, but exact mechanisms remain unknown.