Preclinical validation of novel genotype-specific therapeutic concepts for ATM-deficient pancreatic cancer

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is still dismal despite an increased understanding of its mutational landscape. The phase III POLO trial recently introduced the first effective targeted therapy in PDAC by implementing the PARP inhibitor (PARPi) olaparib as maintenance therapy in germline BRCA1/2 mutated patients. However, BRCA1/2 mutations comprise only a small proportion of genes involved in DNA damage response (DDR), whereas the serine/threonine protein kinase Ataxia-telangiectasia-mutated (ATM) is the most frequently mutated DDR gene. Our lab has previously demonstrated that deletion of ATM in a mouse model of PDAC accelerates tumorigenesis and leads to genomic instable tumors that are vulnerable to inhibition of PARP, ATR and DNA-PKc. Up to our current knowledge the most effective conventional chemotherapy for DDR-defective cancer is platinum-based. The most potent platinum derivate as well as PARPi have not yet been conclusively determined. Based on the Atm^fl/fl; LSL-Kras^G12D/+; Ptf1a^Cre/+ (AKC) and LSL-Kras^G12D/+; Ptf1a^Cre/+ (KC) mouse model primary AKC and KC PDAC cell lines were established. We performed a systematic drug screen on several ATM-deficient (AKC) and ATM-proficient (KC) primary PDAC cells:

(i) to assess genotype-specific vulnerabilities,

(ii) to identify the most effective platinum derivate and PARPi for subsequent synergistic interactions and

(iii) to lower toxicity and increase efficiency upon drug combination.

Interestingly, contrasting with BRCA1/2-mutant PDAC, ATM mutations do not entail higher sensitivity toward platinum-based chemotherapy. Intriguingly, the topoisomerase inhibitors (TOPi) irinotecan and etoposide act genotype-specific and seem to be more efficient than platinum derivates. This is in line with previous findings of selective hypersensitivity due to blockage of replication-dependent strand cleavage upon TOP inhibition. Our findings are supplemented by ATM-deficient and ATM-proficient pancreatic organoids and most efficient synergistic interactions will be validated in vivo. Thus, we provide novel genotype-specific therapeutic concepts to pave the way for clinical trials in ATM-deficient PDAC based on preclinical determination of the most effective PARPi and PARPi-based combinational therapy.

Publication History

Article published online:
08 September 2020