Pancreatic tumors show variable sensitivity to Erlotinib: characterization of the response of cell lines in vitro and patient derived xenografts grown in SCID mice

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EGFR/HER1 overexpression has been observed in 30 to 50% of pancreatic adenocarcinomas. Coexpression of this receptor and at least one of its ligands has been associated with large tumor size, advanced clinical staging, and decreased survival period. This suggests that therapies targeting EGFR/HER1 could be applicable to the treatment of pancreatic cancer. We therefore are evaluating the response of both pancreatic tumor cell lines in in vitro studies and patient derived tumor xenografts to erlotinib, a potent EGFR/HER1 tyrosine kinase inhibitor. In vitro, the pancreatic tumor cell lines BxPC3, CFPAC-1, and HPAC responded well to erlotinib with IC50<9 uM, while ASPC1, MiaPaca and PANC1 were nonresponsive. In order to evaluate the reponsiveness of patient derived tumors, we are using a patient tumor/ SCID mouse xenograft model. The value of this model is that these xenografts maintain the histological features and characteristic heterogeneity of the original patient tumors. Tumor bearing SCID mice were treated with 100mg/kg erlotinib for 21-35 days and tumor growth was evaluated. Of the 5 patient tumors evaluated to date, 2 showed statistically significant growth inhibition as a result of erlotinib treatment, while the growth of 3 was not significantly inhibited. We are currently characterizing these tumors for EGFR expression and the effect of erlotinib on tumor cell proliferation. Some characteristics of these responsive and non-responsive xenografts will be presented. In addition to examining erlotinib as a single agent, combination studies have been initiated to identify agents that can enhance the anti-tumor activity of erlotinib. In in vitro combination studies, some of the pancreatic cell lines showed additive inhibition when combined with the mTOR inhibitor, rapamycin. The responsive and non-responsive pancreatic tumor cell lines and patient tumor xenografts provide material for further study of biomarkers of responsive and non-response to erlotinib. A randomized Phase III clinical study of Tarceva(TM) (erlotinib), in combination with gemcitabine demonstrated a 23.5 percent improvement in overall survival for patients with locally advanced or metastatic pancreatic cancer when compared to patients receiving gemcitabine plus placebo. The results of these preclinical studies will provide valuable information for the design of future clinical studies.