ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

Abstract

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells and associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC..

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…The effects observed with VE-822 were similar to those observed with olaparib, which was employed as a control in these studies [81]. The preclinical efficacy of VE-822 was also assessed in Atm -proficient and -deficient models of Kras -driven PDAC [78]. Specifically, PDAC cells isolated from Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm fl/fl mice were significantly more sensitive to VE-822, than Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm wt/wt controls in vitro [78].…”

“…Thus, it has been speculated that it is the HR defect in BRCA1/2 -mutated cancer cells that confers sensitivity to PARP inhibition [73,74]. In line with this concept, further experiments have shown that PARP inhibition is indeed selectively toxic in cancer cells that harbor aberrations in additional HR genes, such as ATM , RAD51 , RAD54 , DSS1 , RPA1 , NBN , ATR , CHEK1 , CHEK2 , FANCD2 , FANCA and FANCC [77,78,79,80,81]. Given that several critical phenotypes that are associated with BRCA1 or BRCA2 deficiency are also detectable in situations where no germline BRCA1/2 mutation can be detected, the term ‘BRCA-ness' has been coined.…”

“…In addition to PARP inhibitors, HR-defective cancer cells were recently shown to display actionable sensitivities against inhibitors to ATR and DNA-PKcs [78,80,81,86,87,88,89]. DNA-PKcs is a central component of the NHEJ pathway [49].…”

“…The preclinical efficacy of VE-822 was also assessed in Atm -proficient and -deficient models of Kras -driven PDAC [78]. Specifically, PDAC cells isolated from Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm fl/fl mice were significantly more sensitive to VE-822, than Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm wt/wt controls in vitro [78]. Furthermore, these data were validated in a heterotopic transplantation model, where Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm wt/wt -derived tumors were largely resistant against VE-822 or a combination consisting of VE-822 and gemcitabine [78].…”

“…Specifically, PDAC cells isolated from Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm fl/fl mice were significantly more sensitive to VE-822, than Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm wt/wt controls in vitro [78]. Furthermore, these data were validated in a heterotopic transplantation model, where Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm wt/wt -derived tumors were largely resistant against VE-822 or a combination consisting of VE-822 and gemcitabine [78]. In contrast, Ptf1a Cre/wt ;Kras LSL.G12D/wt ;Atm fl/fl -derived tumor growth was substantially delayed when the recipient animals were treated with VE-822 [78].…”