Decreased expression of S100A14 with presence of its genetic variant 425G>A may be associated with an undifferentiated phenotype and poor prognosis in GC.

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.