Disclosure of Erlotinib as a multi-kinase inhibitor in Pancreatic Ductal Adenocarcinoma

A placebo-controlled phase III trial demonstrated that the EGFR inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC) subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work we observed high erlotinib IC50 values in a panel of human and murine PDAC cell lines. Using EGFR siRNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets we used an unbiased chemical proteorriics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture (SILAC). In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (Kd 0.09 mu M to 0.358 mu M) than the EGFR (Kd 0.434 mu M). We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multi-kinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.