Abstract

<div>Abstract<p><b>Purpose:</b> The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models.</p><p><b>Experimental Design:</b> We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)–proficient and –deficient pancreatic cancer cells and assessed Rad51 focus formation. <i>In vivo</i>, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776.</p><p><b>Results:</b> We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. <i>In vivo</i>, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an <i>ex vivo</i> platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer.</p><p><b>Conclusions:</b> Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer. <i>Clin Cancer Res; 19(16); 4412–21. ©2013 AACR</i>.</p></div>

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