TY - JOUR
T1 - Monomer preference of EGFR tyrosine kinase inhibitors influences the synergistic efficacy of combination therapy with cetuximab
AU - Oashi, Ayano
AU - Yasuda, Hiroyuki
AU - Kobayashi, Keigo
AU - Tani, Tetsuo
AU - Hamamoto, Junko
AU - Masuzawa, Keita
AU - Manabe, Tadashi
AU - Terai, Hideki
AU - Ikemura, Shinnosuke
AU - Kawada, Ichiro
AU - Naoki, Katsuhiko
AU - Soejima, Kenzo
N1 - Funding Information:
We would like to thank Professor Tomoko Betsuyaku for financial assistance and technical advice. We are grateful to Ms. Mikiko Shibuya and Ms. Chinatsu Yonekawa for their excellent technical assistance. We are also grateful to the Collaborative Research Resources at the Keio University School of Medicine (Tokyo, Japan) for assistance with cell sorting. This work was supported, in part, by Japan Society for the Promotion of Science (JSPS; 15K09229, to K. Soejima; 17K09667, to H. Yasuda; and 18K08184, to H. Terai). This work was supported, in part, by Takeda Science Foundation (to H. Yasuda and H. Terai).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - EGFR-mutated lung cancer is a significant subgroup of non–small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR-mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR, including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer–dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR. Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI–induced dimerization. By shifting the monomer–dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer–dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI–refractory non–small cell lung cancer.
AB - EGFR-mutated lung cancer is a significant subgroup of non–small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR-mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR, including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer–dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR. Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI–induced dimerization. By shifting the monomer–dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer–dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI–refractory non–small cell lung cancer.
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U2 - 10.1158/1535-7163.MCT-18-1036
DO - 10.1158/1535-7163.MCT-18-1036
M3 - Article
C2 - 31253648
AN - SCOPUS:85071787855
VL - 18
SP - 1593
EP - 1601
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 9
ER -