Abstract B42: ATM deficiency sensitizes gastric cancer cells to the PARP inhibitior olaparib

Abstract

Ataxia telangiectasia mutated (ATM) is a protein kinase that regulates cell-cycle checkpoints, DNA repair and recombination (1). It has been shown that ATM interacts with and regulates NBS1 and BRCA complex which is essential for the homologous recombination (HR) repair in response to the DNA double-strand break (DSB) damage (2). These observations suggest that tumor cells with defective ATM expression or activity subsequently leading to HR deficiency are likely more sensitive to the targeted therapeutic/chemotherapeutic agents that cause the accumulation of DNA DSBs during replication. To test this, we studied the growth inhibitory effects of olaparib (AZD2281; KU-0059436) and SN-38 (the active metabolite of Irinotecan) on gastric cancer (GC) cells with reduced ATM expression. Olaparib is a potent oral inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), which has selective antitumor activity in cancers associated with BRCA1 and BRCA2 mutations (3). Our study here showed that 6 out of 7 GC cell lines with low or no expression of ATM are sensitive to olaparib inhibition with IC50s ≤ 1uM as measured by clonogenic survival assays. In contrast, the majority of other GC cell lines positive for ATM expression (11 out of 13) are less sensitive (1uM < IC50 ≤ 1.5uM) or resistant (IC50 > 1.5uM) to olaparib with only 2 of 13 lines sensitive. Similar correlation was also observed in these GC cell lines between reduced ATM expression and sensitivity to SN-38 treatment. In addition, combination of olaparib and SN-38 had a synergistic and selective inhibitory effect on cell growth of GC cells with low/no expression of ATM. These data suggest that loss of ATM in GC cell can sensitize their cellular response to olaparib or/and SN-38. Next, we asked whether this finding has clinical relevance in GC therapy. The tumor and tumor adjacent tissue specimens from more than 100 patients with gastric cancer were analyzed for ATM expression by immunohistochemistry. 22% (24/111) of the gastric tumor specimens were found stained ATM negative while the negative rate in the adjacent tissues was only 4% (1/26). These results suggested that loss of ATM expression is frequently associated with gastric tumorigenesis. Loss of ATM function may serve as an important tumor biomarker in GC and a PARP inhibitor as monotherapy or in combination with chemotherapy provides a promising therapeutic in this disease segment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B42.

Concordance of ATM (Ataxia Telangiectasia Mutated) Immunohistochemistry between Biopsy or Metastatic Tumor Samples and Primary Tumors in Gastric Cancer Patients

“…ATM deficiency has been shown to sensitize lymphoid tumor cells [6,7] to the PARP inhibitor olaparib, and sensitivity to gastric cell lines was also suggested to be due to low levels of ATM expression [10]. We assessed the concordance in ATM IHC between preoperative endoscopic biopsy or metastatic tumor samples and whole tissue or primary tumor samples in two independent cohorts.…”

“…ATM mRNA and protein levels were found to be decreased in gastric cancers compared to normal samples, phosphorylated ATM was consistently present in gastric cancers, and low levels of phosphorylated ATM were significantly correlated with poor differentiation, lymph node metastasis and poor 5-year survival [9]. Guo et al [10] observed that ATM deficiency sensitizes cells to the growth-inhibitory effects of olaparib and SN-38 (the active metabolite of irinotecan) in gastric cancer cells with reduced ATM expression.…”

Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing

“…Despite these prerogatives, data in clear favor of platinum-based treatments are contradictory in GC [85]. Preclinical models suggest an effect of poly(ADPribose) polymerase (PARP) inhibitors (PARPi) in GC cells, confirmed by the promising results of the randomized phase II trial in advanced GC designed to demonstrate the safety and efficacy of adding olaparib to taxane-based chemotherapy [82,86]. The failure of the phase III GOLD trial in advanced GC in the subgroup of ATM low patients did not lead to further development of PARPi in early stages and implied that in GC, the DDR mechanisms have a complexity that we do not yet fully understand [87].…”

Low ATM expression and progression-free and overall survival in advanced gastric cancer patients treated with first-line XELOX chemotherapy

“…Low expression of ATM in GC is associated with poorlydifferentiated histology, lymph node involvement, and worse overall 5-year survival among patients undergoing curative surgical resection (11). Pre-clinical models have suggested increased sensitivity of ATM deficient cells to inhibition with olaparib and SN-38 though platinum associations remain understudied (12). Recently, the phase III GOLD trial failed to show a survival benefit for olaparib in unselected advanced GC progressing after first-line therapy.…”