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HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers

Research output: Contribution to journalArticlepeer-review

Bob T Li, Flavia Michelini, Sandra Misale, Emiliano Cocco, Laura Baldino, Yanyan Cai, Sophie Shifman, Hai-Yan Tu, Mackenzie L Myers, Chongrui Xu, Marissa Mattar, Inna Khodos, Megan Little, Besnik Qeriqi, Gregory Weitsman, Clare J Wilhelm, Alshad S Lalani, Irmina Diala, Rachel A Freedman, Nancy U Lin & 29 more David B Solit, Michael F Berger, Paul R Barber, Tony Ng, Michael Offin, James M Isbell, David R Jones, Helena A Yu, Sheeno Thyparambil, Wei-Li Liao, Anuja Bhalkikar, Fabiola Cecchi, David M Hyman, Jason S Lewis, Darren J Buonocore, Alan L Ho, Vicky Makker, Jorge S Reis-Filho, Pedram Razavi, Maria E Arcila, Mark G Kris, John T Poirier, Ronglai Shen, Junji Tsurutani, Gary A Ulaner, Elisa de Stanchina, Neal Rosen, Charles M Rudin, Maurizio Scaltriti

Original languageEnglish
Pages (from-to)674-687
Number of pages14
JournalCancer discovery
Volume10
Issue number5
Early online date25 Mar 2020
DOIs
E-pub ahead of print25 Mar 2020
Published1 May 2020

Bibliographical note

Copyright ©2020, American Association for Cancer Research.

King's Authors

Abstract

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or-mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGnIFICAnCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.

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