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Memo<\/i>, 15<\/b>, 125\u2013128 (2022).","DOI":"10.1007\/s12254-021-00780-8"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6) Grairi M, Le Borgne M. Antibody-drug conjugates: prospects for the next generation. Drug Discov. Today<\/i>, 29<\/b>, 104241 (2024).","DOI":"10.1016\/j.drudis.2024.104241"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7) Cort\u00e9s J, Kim S-B, Chung W-P, et al<\/i>. Trastuzumab deruxtecan versus<\/i> trastuzumab emtansine for breast cancer. N. Engl. J. Med.<\/i>, 386<\/b>, 1143\u20131154 (2022).","DOI":"10.1056\/NEJMoa2115022"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8) Shitara K, Bang Y-J, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med.<\/i>, 382<\/b>, 2419\u20132430 (2020).","DOI":"10.1056\/NEJMoa2004413"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9) Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, Soma M, Okamoto H, Oitate M, Arakawa S, Hirai T, Atsumi R, Nakada T, Hayakawa I, Abe Y, Agatsuma T. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res.<\/i>, 22<\/b>, 5097\u20135108 (2016).","DOI":"10.1158\/1078-0432.CCR-15-2822"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10) Catapano C, Rahm JV, Omer M, Teodori L, Kjems J, Dietz MS, Heilemann M. Biased activation of the receptor tyrosine kinase HER2. Cell. Mol. Life Sci.<\/i>, 80<\/b>, 158 (2023).","DOI":"10.1007\/s00018-023-04806-8"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11) Joshi SK, Keck JM, Eide CA, Bottomly D, Traer E, Tyner JW, McWeeney SK, Tognon CE, Druker BJ. ERBB2\/HER2 mutations are transforming and therapeutically targetable in leukemia. Leukemia<\/i>, 34<\/b>, 2798\u20132804 (2020).","DOI":"10.1038\/s41375-020-0844-7"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12) Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J.<\/i>, 19<\/b>, 3159\u20133167 (2000).","DOI":"10.1093\/emboj\/19.13.3159"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Carneiro BA, Papadopoulos KP, Strickler JH, et al<\/i>. Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: safety, pharmacokinetics, and antitumor activity in advanced glioblastoma. Neurooncol. Adv.<\/i>, 5<\/b>, vdac183 (2023).","DOI":"10.1093\/noajnl\/vdac183"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14) Reardon DA, Lassman AB, van den M, Kumthekar P, Merrell R, Scott AM, Fichtel L, Sulman EP, Gomez E, Fischer J, Lee HJ, Munasinghe W, Xiong H, Mandich H, Roberts-Rapp L, Ansell P, Holen KD, Gan HK. Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. Neuro Oncol.<\/i>, 19<\/b>, 965\u2013975 (2017).","DOI":"10.1093\/neuonc\/now257"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15) Gan HK, Reardon DA, Lassman AB, Merrell R, van den Bent M, Butowski N, Lwin Z, Wheeler H, Fichtel L, Scott AM, Gomez EJ, Fischer J, Mandich H, Xiong H, Lee HJ, Munasinghe WP, Roberts-Rapp LA, Ansell PJ, Holen KD, Kumthekar P. Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Neuro Oncol.<\/i>, 20<\/b>, 838\u2013847 (2018).","DOI":"10.1093\/neuonc\/nox202"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16) Yu J, Fang T, Yun C, Liu X, Cai X. Antibody-drug conjugates targeting the human epidermal growth factor receptor family in cancers. Front. Mol. Biosci.<\/i>, 9<\/b>, 847835 (2022).","DOI":"10.3389\/fmolb.2022.847835"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol. Oncol.<\/i>, 12<\/b>, 3\u201320 (2018).","DOI":"10.1002\/1878-0261.12155"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18) Goh LK, Sorkin A. Endocytosis of receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol.<\/i>, 5<\/b>, a017459 (2013).","DOI":"10.1101\/cshperspect.a017459"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Tomas A, Futter CE, Eden ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol.<\/i>, 24<\/b>, 26\u201334 (2014).","DOI":"10.1016\/j.tcb.2013.11.002"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20) Caldieri G, Malabarba MG, Di Fiore PP, Sigismund S. EGFR trafficking in physiology and cancer. Prog. Mol. Subcell. Biol.<\/i>, 57<\/b>, 235\u2013272 (2018).","DOI":"10.1007\/978-3-319-96704-2_9"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21) Zhou Y, Takahashi JI, Sakurai H. New directions for advanced targeting strategies of EGFR signaling in cancer. Biol. Pharm. Bull.<\/i>, 47<\/b>, 895\u2013903 (2024).","DOI":"10.1248\/bpb.b23-00924"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Yamagishi N, Takahashi JI, Zhou Y, Yokoyama S, Makino T, Shimizu T, Sakurai H. Non-canonical regulation of EGFR by the air pollutant 9,10-phenanthrenequinone. Biol. Pharm. Bull.<\/i>, 45<\/b>, 1553\u20131558 (2022).","DOI":"10.1248\/bpb.b22-00489"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23) Haryuni RD, Tanaka T, Takahashi JI, Onuma I, Zhou Y, Yokoyama S, Sakurai H. Temozolomide induces endocytosis of EGFRvIII via<\/i> p38-mediated non-canonical phosphorylation in glioblastoma cells. Biol. Pharm. Bull.<\/i>, 44<\/b>, 1681\u20131687 (2021).","DOI":"10.1248\/bpb.b21-00371"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24) Tanaka T, Zhou Y, Ozawa T, Okizono R, Banba A, Yamamura T, Oga E, Muraguchi A, Sakurai H. Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation. J. Biol. Chem.<\/i>, 293<\/b>, 2288\u20132301 (2018).","DOI":"10.1074\/jbc.M117.811299"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25) Zhou Y, Sakurai H. New trend in ligand-induced EGFR trafficking: a dual-mode clathrin-mediated endocytosis model. J. Proteomics<\/i>, 255<\/b>, 104503 (2022).","DOI":"10.1016\/j.jprot.2022.104503"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S. Clathrin-independent endocytosis of ubiquitinated cargos. Proc. Natl. Acad. Sci. U.S.A.<\/i>, 102<\/b>, 2760\u20132765 (2005).","DOI":"10.1073\/pnas.0409817102"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27) Tanaka T, Ozawa T, Oga E, Muraguchi A, Sakurai H. Cisplatin-induced non-canonical endocytosis of EGFR via<\/i> p38 phosphorylation of the C-terminal region containing Ser-1015 in non-small cell lung cancer cells. Oncol. Lett.<\/i>, 15<\/b>, 9251\u20139256 (2018).","DOI":"10.3892\/ol.2018.8485"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28) Perez Verdaguer M, Zhang T, Paulo JA, Gygi S, Watkins SC, Sakurai H, Sorkin A. Mechanism of p38 MAPK-induced EGFR endocytosis and its crosstalk with ligand-induced pathways. J. Cell Biol.<\/i>, 220<\/b>, e202102005 (2021).","DOI":"10.1083\/jcb.202102005"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29) Nishimura M, Shin M-S, Singhirunnusorn P, Suzuki S, Kawanishi M, Koizumi K, Saiki I, Sakurai H. TAK1-mediated serine\/threonine phosphorylation of epidermal growth factor receptor via<\/i> p38\/extracellular signal-regulated kinase: NF-\u03baB-independent survival pathways in tumor necrosis factor alpha signaling. Mol. Cell. Biol.<\/i>, 29<\/b>, 5529\u20135539 (2009).","DOI":"10.1128\/MCB.00375-09"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30) Singhirunnusorn P, Ueno Y, Matsuo M, Suzuki S, Saiki I, Sakurai H. Transient suppression of ligand-mediated activation of epidermal growth factor receptor by tumor necrosis factor-\u03b1 through the TAK1-p38 signaling pathway. J. Biol. Chem.<\/i>, 282<\/b>, 12698\u201312706 (2007).","DOI":"10.1074\/jbc.M608723200"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Takahashi J, Nakamura S, Onuma I, Zhou Y, Yokoyama S, Sakurai H. Synchronous intracellular delivery of EGFR-targeted antibody-drug conjugates by p38-mediated non-canonical endocytosis. Sci. Rep.<\/i>, 12<\/b>, 11561 (2022).","DOI":"10.1038\/s41598-022-15838-8"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32) Noro R, Gemma A, Kosaihira S, Kokubo Y, Chen M, Seike M, Kataoka K, Matsuda K, Okano T, Minegishi Y, Yoshimura A, Kudoh S. Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. BMC Cancer<\/i>, 6<\/b>, 277 (2006).","DOI":"10.1186\/1471-2407-6-277"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33) Ko R, Kenmotsu H, Serizawa M, Koh Y, Wakuda K, Ono A, Taira T, Naito T, Murakami H, Isaka M, Endo M, Nakajima T, Ohde Y, Yamamoto N, Takahashi K, Takahashi T. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. BMC Cancer<\/i>, 16<\/b>, 864 (2016).","DOI":"10.1186\/s12885-016-2902-0"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34) Azuma K, Kawahara A, Sonoda K, Nakashima K, Tashiro K, Watari K, Izumi H, Kage M, Kuwano M, Ono M, Hoshino T. FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget<\/i>, 5<\/b>, 5908\u20135919 (2014).","DOI":"10.18632\/oncotarget.1866"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35) Park S, Lee MH, Seong M, Kim ST, Kang JH, Cho BC, Lee KH, Cho EK, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann. Oncol.<\/i>, 31<\/b>, 1397\u20131404 (2020).","DOI":"10.1016\/j.annonc.2020.06.017"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36) Soria J-C, Ohe Y, Vansteenkiste J, et al<\/i>. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med.<\/i>, 378<\/b>, 113\u2013125 (2018).","DOI":"10.1056\/NEJMoa1713137"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37) Michelon I, Vilbert M, Castro C, Stecca C, Dacoregio MI, Rizzo MM, Cordeiro De Lima VC. Retreatment with EGFR inhibitor in non-small cell lung cancer patients previously exposed to EGFR-TKI: a systematic review and meta-analysis. J. Clin. Oncol.<\/i>, 41<\/b> (16_suppl), e21159 (2023).","DOI":"10.1200\/JCO.2023.41.16_suppl.e21159"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38) Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T, Takigawa N, Takata M, Kiura K, Tanimoto M. Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line. Cancer Res.<\/i>, 67<\/b>, 7807\u20137814 (2007).","DOI":"10.1158\/0008-5472.CAN-07-0681"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Itai S, Yamada S, Kaneko MK, Chang YW, Harada H, Kato Y. Establishment of EMab-134, a sensitive and specific anti-epidermal growth factor receptor monoclonal antibody for detecting squamous cell carcinoma cells of the oral cavity. Monoclon. Antib. Immunodiagn. Immunother.<\/i>, 36<\/b>, 272\u2013281 (2017).","DOI":"10.1089\/mab.2017.0042"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40) Refaat A, Zhou Y, Suzuki S, Takasaki I, Koizumi K, Yamaoka S, Tabuchi Y, Saiki I, Sakurai H. Distinct roles of transforming growth factor-\u03b2-activated kinase 1 (TAK1)-c-Rel and interferon regulatory factor 4 (IRF4) pathways in human T cell lymphotropic virus 1-transformed T helper 17 cells producing interleukin-9. J. Biol. Chem.<\/i>, 286<\/b>, 21092\u201321099 (2011).","DOI":"10.1074\/jbc.M110.200907"},{"key":"41","doi-asserted-by":"crossref","unstructured":"41) Chavez-Dominguez R, Aguilar-Cazares D, Perez-Medina M, Avila-Rios S, Soto-Nava M, Mendez-Tenorio A, Islas-Vazquez L, Benito-Lopez JJ, Galicia-Velasco M, Lopez-Gonzalez JS. Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma. Front. Oncol.<\/i>, 13<\/b>, 1208403 (2023).","DOI":"10.3389\/fonc.2023.1208403"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42) Griesinger F, Korol EE, Kayaniyil S, Varol N, Ebner T, Goring SM. Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: A meta-analysis. Lung Cancer<\/i>, 135<\/b>, 196\u2013204 (2019).","DOI":"10.1016\/j.lungcan.2019.07.010"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43) Planchard D, J\u00e4nne PA, Cheng Y, et al<\/i>. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N. Engl. J. Med.<\/i>, 389<\/b>, 1935\u20131948 (2023).","DOI":"10.1056\/NEJMoa2306434"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44) Esteban-Fern\u00e1ndez D, Verdaguer JM, Ram\u00edrez-Camacho R, Palacios MA, G\u00f3mez-G\u00f3mez MM. Accumulation, fractionation, and analysis of platinum in toxicologically affected tissues after cisplatin, oxaliplatin, and carboplatin administration. J. Anal. 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