Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591184
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: MAEMODNO MAKOTO 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 特任研究員 (40344676)
• Co-Investigator(Kenkyū-buntansha): TANAKA Nobuyuki 地方独立法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 部長 (60280872)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 癌 / 非小細胞肺癌 / 治療法

Outline of Final Research Achievements

TKIs are effective for NSCLC patients with EGFR-activating mutations. However, these patients eventually develop resistance, most frequently by T790M mutation. Combining a second-generation TKI with an anti-EGFR monoclonal antibody has been shown to improve clinical outcomes, although the mechanism remains elusive. To investigate this mechanism, we used EGFR-negative K562 cells. Double-mutant EGFRs were moderately sensitive to afatinib, but minimally affected by cetuximab. Combining afatinib and cetuximab synergistically increased cytotoxity for K562 cells carrying double-mutant EGFRs. Apoptosis in these cells was preceded by induction of BIM and activation of Caspase-3 and PARP. Afatinib induced EGFR recycling to the cell surface, leading to the cetuximab-mediated recognition and subsequent degradation. These results suggest that the synergistic effect exerted by afatinib and cetuximab against NSCLCs has a potential in the future clinical application.

Free Research Field

呼吸器内科学