Abstract 5600: Acquired resistance of pancreatic cancers to combination therapy with lapatinib plus the MEK 1/2 inhibitor GSK1120212: Using a murine orthotopic xenograft model to identify resistance pathways
Authors: Lindberg James M. , Walters Dustin M. , Adair Sara J. , Xin Wenjun , Edik Blais , Stokes Jayme B. , Borgman Cheryl A. , Stelow Edward B. , Sanoff Hanna K. , Lee Jae K. , Papin Jason A. , Parsons J. Thomas , Bauer Todd W. 
Published: August 2012

Abstract
Background: The high incidence of KRAS mutations in human pancreatic cancers has driven the testing of MEK1/2 inhibitors (e.g. GSK1120212) in clinical trials for pancreatic cancer. We have recently shown that human patient-derived tumors expressing activated epidermal growth factor (EGF)/HER2 receptors exhibit enhanced response to combination therapy with GSK1120212 and lapatinib, using a mouse xenograft model. A phase I clinical trial of GSK1120212 plus lapatinib is now underway. We report here the analysis of tumors that have acquired resistance to this therapy in the setting of the mouse xenograft model with the goal of identifying additional effective combination therapies and improved strategies for treatment of patients with resistant disease. Methods: Three patient-derived pancreatic cancer xenografts expressing either mutant or wild type KRAS and activated EGF/HER2 receptors were implanted orthotopically in nude mice and treated with combination lapatinib (EGFR/HER2 inhibitor) and GSK1120212 (MEK1/2 inhibitor). Tumor volume was assessed by sequential MRI. Following treatment, tumors were reimplanted in second and third generation mice and retreated to generate therapy-resistant tumors. Drug-resistant and drug-naïve tumors were compared using gene expression profiling, protein kinase arrays and Western blotting analysis. Results: Acquired resistance developed in all three tumor xenografts. Gene expression profiling identified multiple genes whose expression changed in response to drug treatment. Western blot analysis of tumor lysates from resistant and naive tumors revealed examples of select resistant tumors with either sustained activation of ERK1/2 or inactivation of ERK1/2 in the presence of inhibitor. Individual resistant tumors exhibiting inactivation of ERK1/2 exhibited increased activity of alternate survival signaling pathways including increased pAkt, pp38, pJNK, and pGSK3β levels relative to drug naïve control tumors. Phospho-RTK array analysis revealed increased pFGFR1 and pVEGFR1 levels in select resistant tumors suggesting a possible role for up-regulated RTK signaling in acquired resistance. Conclusions: Using an orthotopic murine model bearing patient-derived pancreatic cancer xenografts, we have developed a model of acquired resistance to lapatinib plus GSK1120212. Interrogation of comparative gene expression and phospho-protein studies revealed alterations in signaling pathways that may contribute to drug resistance. Current studies aim to exploit these pathways to 1) derive strategies for treatment of drug-resistant tumors, and 2) develop additional rational combinatorial therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5600. doi:1538-7445.AM2012-5600