Introduction:
Pancreatic ductal adenocarcinoma (PDAC) bears a high accumulation of oncogenic mutations.
Recent sequencing studies found Ataxia-Telangiectasia Mutated (ATM) mutated in up
to 8% of human PDACs, primarily within the genomic unstable subtype. In line, we previously
showed that the loss of ATM accelerates EMT and promotes genomic instability. The
altered genomic integrity sensitizes ATM-mutated PDAC to new tailored therapy strategies
like PARP- and ATR- inhibition. However, these treatment strategies tend to show early
resistance. Here we aim to unravel novel therapy approaches to overcome chemoresistance
and widen the therapeutic spectrum in ATM-mutated PDAC.
Methods:
Based on the Atm
F/F, Kras
+/G12D, Ptf1a-Cre
+/- (AKC) and Kras
+/G12D, Ptf1a-Cre
+/- (KC) mouse model primary AKC and KC PDAC cell lines were established. A systematic
drug screen was done in vitro. Most promising therapy approaches were transferred and evaluated in an in vivo setting.
Results:
Within the drug screen a variety of effectors that specifically inhibit growth in vitro in AKC and KC PDAC cell lines could be shown, although without genotype specificity.
As an example JAK- and BMP4-inhibition had equal effects in AKC and KC cell lines.
Systematic screening on further combinational approaches could reveal genotype specific
synthetic lethality therapies for AKC cell lines, e.g. DNA-PKC inhibition. In deep
analysis showed novel signaling networks within ATM-depleted PDAC allowing completely
new treatment strategies. Consequently, new combination strategies were assessed and
revealed significant effects on cell and tumor growth. Interestingly, these effects
were largely based on drugs that already failed in not selected PDAC trials or are
uncommon in therapy like topoisomerase inhibitors.
Conclusion:
Based on a novel genomic unstable, ATM-depleted PDAC model we could identify new targeted
therapy strategies. This may pave the way to clinical trials in this subgroup of PDAC
patients.
