Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells

Abstract

Background:The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker.Methods:We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively.Results:At 200 n, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC50 values of 11 and 1200 n. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth.Conclusion:The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.

Expression of Tumor Necrosis Factor-alpha-induced Protein 8 in Pancreas Tissues and its Correlation with Epithelial Growth Factor Receptor Levels

“…EGFR (ErbB-1) was found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors. Decreasing the expression level of EGFR protein contributes to EGFR targeted therapy of cancers (Ioannou et al, 2011;Xu et al, 2011). So EGFR is a legitimate therapeutic target, and there is a outline of endocytic escape of EGFRs in cancer with special attention towards advances in various approaches adopted for EGFR targeting (Aggarwal et al, 2011).…”

Functionalized gold nanoparticles improve afatinib delivery into cancer cells

“…Indeed, afatinib has been approved for first-line treatment of patients with metastatic NSCLC, whose tumours have specific mutations in EGFR, namely exon 19 deletions or exon 21 (L858R) substitutions [29]. Some reports also suggest that afatinib can be a promising inhibitor against human pancreatic tumour cells [24,30,31]. Positive results have also been reported in the therapy of other advanced solid tumours, when afatinib is given in combination with conventional chemotherapeutic agents [26,32].…”

“…is an aniline-quinazoline that irreversibly binds to the intracellular tyrosine kinase domain of the ErbB family of receptors (acting as a pan-ErbB inhibitor) [24][25][26].…”

Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells

“…Afatinib is an inhibitor which inhibits EGFR1, HER2 and EGFR4 (Ioannou et al, 2011;Seshacharyulu et al, 2015). Afatinib has been evaluated in combination with paclitaxel in clinical trial NCT01728818 for PDAC patients.…”