Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.
Gut
; 70(4): 743-760, 2021 04.
Article
in En
| MEDLINE
| ID: mdl-32873698
ABSTRACT
OBJECTIVE:
ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).DESIGN:
Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.RESULTS:
Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance.CONCLUSION:
Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Adenocarcinoma
/
Carcinoma, Pancreatic Ductal
/
Homologous Recombination
/
Ataxia Telangiectasia Mutated Proteins
/
Poly(ADP-ribose) Polymerase Inhibitors
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Gut
Year:
2021
Document type:
Article
Affiliation country: