title: Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer.
abstract: Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure-activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.|Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Uchibori
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Inase
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Araki
authors.affiliation: Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kamada
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.affiliation: RIKEN Advanced Institute for Computational Science, 7-1-26 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.|Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Ryohei
authors.identifier: 0000-0001-7394-895X
authors.initials: R
authors.lastname: Katayama
mesh_terms: D000178:Acrylamides; D000814:Aniline Compounds; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D000077544:Panitumumab; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D009943:Organophosphorus Compounds; D000077544:Panitumumab; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000596361:osimertinib; D007211:Indoles; C512478:EGFR protein, human; C000598580:brigatinib