Abstract 2378: Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss.

Abstract

Abstract Gemcitabine, a pyrimidine analog/antimetabolite, is commonly used to treat breast, lung, head and neck, pancreatic, ovarian, biliary, urinary bladder, and cervical carcinomas. Gemcitabine inhibits DNA synthesis by direct inhibition of ribonucleotide reductase by its metabolite, gemcitabine diphosphate, and the incorporation of its active form, gemcitabine triphosphate into the elongating DNA strand, resulting in chain termination. Gemcitabine-induced DNA damage leads to activation of the ATR/CHK1 pathway and S-phase cell cycle arrest. Our previous studies showed that carcinoma cells with our biomarker (distal 11q loss) overexpress ATR and CHK1, resulting in decreased sensitivity to ionizing radiation in biomarker-positive head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) cell lines. Several studies in the literature have shown that inhibition of CHK1 increases the sensitivity of tumor cell lines to replication inhibitors, including gemcitabine. In pancreatic cancer cell lines, small molecule inhibitor (SMI)-mediated disruption of CHK1 signaling has been reported to potentiate the cytotoxic effect of gemcitabine. Based on the literature and our previous findings, we now report that biomarker-positive HNSCC and NSCLC cell lines also show ATR/CHK1 upregulation and decreased sensitivity to gemcitabine, Further, we observed that siRNA knockdown of the ATR/CHK1 pathway and SMI inhibition of CHK1 signaling in HNSCC and NSCLC cell lines increase their sensitivity to treatment with gemcitabine. Our previous results showed increased efficacy of ionizing radiation combined with CHK1 inhibition in biomarker-positive cell lines; our new results show increased efficacy of gemcitabine combined with CHK1 inhibition in biomarker-positive HNSCC and NSCLC cell lines. These results provide further support for combining CHK1-targeted therapy with standard therapy in conjunction with an appropriate companion diagnostic biomarker, like distal 11q loss. As is the case with other targeted therapies, biomarker-based selection of the right drug for the right patient appears to increase therapeutic efficacy. Citation Format: Madhav Sankunny, Rahul A. Parikh, Susanne M. Gollin. Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2378. doi:10.1158/1538-7445.AM2013-2378