Beyond BRCAness: ATM pathway defects confer sensitivity to topoisomerase I inhibition

The ATM pathway is crucial for the cellular response to DNA damage. Mutations in ATM and CHEK2 occur in cancers such as pancreatic ductal adenocarcinoma (PDAC) and alter this pathway in an important minority (~5–10%) of patients. ATM/CHEK2 –mutant PDAC may not exhibit homologous recombination repair (HRR) deficiency and, unlike patients with BRCA mutations, these defects may not consistently sensitize tumors to platinum or PARP-inhibitor therapy. Preliminary studies suggest that certain types of ATM pathway dysfunction may prevent topoisomerase I–DNA adduct removal, possibly producing genomic instability that is sensitive to topoisomerase I inhibitors such as irinotecan. We analyzed treatment and outcome data for patients with ATM/CHEK2 -mutated advanced/metastatic PDAC using an institutional real-world database (48 chemotherapy lines; 16 patients). In addition, PANC-1 isogenic cell lines were CRISPR-edited for homozygous and heterozygous ATM knockout (Synthego Corporation), allele-verified by whole-exome sequencing, and tested for colony formation, proliferation, and viability after exposure to SN-38, the active metabolite of irinotecan (SN-38 was used for in vitro experiments because irinotecan is metabolized to SN-38 by the liver). Irinotecan-containing therapy out-performed other treatment types (median second line for each), including platinum/PARP-inhibitor-containing regimens; median progression-free survival (PFS) was 11.5 versus 3 months ( p < 0.001). Moreover, in vitro studies using the CRISPR-edited isogenic panel demonstrated increasing vulnerability to SN-38 with increasing ATM loss, both in colony formation ( ATM -/- half-maximal inhibitory concentration [IC50]=0.3 nM; ATM +/-, IC50 = 0.8 nM; wild-type, IC50 = 7 nM) and in proliferation/viability assays (all p < 0.01). Real-world data show that patients with ATM/CHEK2 -mutated PDAC achieved longer disease control on irinotecan- than on platinum/PARP-inhibitor-based therapy. Moreover, CRISPR-edited heterozygous and homozygous ATM -deleted PDAC cell lines demonstrated correspondingly increased growth/viability sensitivity to the active irinotecan metabolite SN-38. Topoisomerase I inhibitors merit prospective investigation in ATM pathway-mutated PDAC.