Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status.

BACKGROUND: Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients.

OBJECTIVE: Here we investigated the activity of afatinib, a second-generation irreversible pan-EGFR family kinase inhibitor, alone or in combination with ionizing radiation, toward pancreatic cancer cells.

METHODS: The influence of afatinib on cell proliferation, cell cycle distribution, clonogenic survival, nuclear fragmentation, ploidy, and centrosome amplification following irradiation was determined. Expression and phosphorylation of HER receptors, Akt, DNA-PKcs, and ERK1/2 was characterized by Western blot analysis.

RESULTS: Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 (KRAS (wt)) and Capan-2 (KRAS (mut)) cells, both of which express high levels of EGFR, HER2, and HER3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells, prevented the radio-induced phosphorylation of Akt, and induced mitotic catastrophe following irradiation. In comparison, Panc-1 cells (KRAS (mut)) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization.

LIMITATIONS: These results must be confirmed in vivo.

CONCLUSIONS: Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR, HER2, and HER3 receptors, but not with KRAS status.