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Triplet therapy with afatinib, cetuximab and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo.

Triplet therapy with afatinib, cetuximab and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo.
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Kudo K, Ohashi K, Makimoto G, Higo H, Kato Y, Kayatani H, Kurata Y, Takami Y, Minami D, Ninomiya T, Kubo T, Ichihara E, Sato A, Hotta K, Yoshino T, Tanimoto M, Kiura K,


Kudo K, Ohashi K, Makimoto G, Higo H, Kato Y, Kayatani H, Kurata Y, Takami Y, Minami D, Ninomiya T, Kubo T, Ichihara E, Sato A, Hotta K, Yoshino T, Tanimoto M, Kiura K, (click to view)

Kudo K, Ohashi K, Makimoto G, Higo H, Kato Y, Kayatani H, Kurata Y, Takami Y, Minami D, Ninomiya T, Kubo T, Ichihara E, Sato A, Hotta K, Yoshino T, Tanimoto M, Kiura K,

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Molecular oncology 2017 04 07() doi 10.1002/1878-0261.12063
Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFR(T)(790M) mutations in clinical trials. The effect of bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dosage of afatinib and cetuximab could be reduced by combination with bevacizumab, and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFR(L)(858R+T790M) and RPC-9-harboring EGFR(19)(DEL)(+T790M) , we tested the efficacy of the triplet therapy with a modified dosage of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single- or double-therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFR(T)(790M) mutations. Therefore, clinical trials of this combination therapy are warranted.

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