Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors.
Proc Natl Acad Sci U S A
; 117(42): 26356-26365, 2020 10 20.
Article
in En
| MEDLINE
| ID: mdl-33020270
ABSTRACT
Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phthalazines
/
Piperazines
/
Morpholines
/
Chromones
/
Carcinoma, Hepatocellular
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2020
Type:
Article
Affiliation country:
China