Changing therapeutic facets in genomic unstable pancreatic cancer

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.