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

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

Authors:	Li, B. T.; Michelini, F.; Misale, S.; Cocco, E.; Baldino, L.; Cai, Y.; Shifman, S.; Tu, H. Y.; Myers, M. L.; Xu, C.; Mattar, M.; Khodos, I.; Little, M.; Qeriqi, B.; Weitsman, G.; Wilhem, C. J.; Lalani, A. S.; Diala, I.; Freedman, R. A.; Lin, N. U.; Solit, D. B.; Berger, M. F.; Barber, P. R.; Ng, T.; Offin, M.; Isbell, J. M.; Jones, D. R.; Yu, H. A.; Thyparambil, S.; Liao, W. L.; Bhalkikar, A.; Cecchi, F.; Hyman, D. M.; Lewis, J. S.; Buonocore, D. J.; Ho, A. L.; Makker, V.; Reis-Filho, J. S.; Razavi, P.; Arcila, M. E.; Kris, M. G.; Poirier, J. T.; Shen, R.; Tsurutani, J.; Ulaner, G. A.; de Stanchina, E.; Rosen, N.; Rudin, C. M.; Scaltriti, M.
Article Title:	HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers
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.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627. ©2020 American Association for Cancer Research.
Journal Title:	Cancer Discovery
Volume:	10
Issue:	5
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2020-05-01
Start Page:	674
End Page:	687
Language:	English
DOI:	10.1158/2159-8290.Cd-20-0215
PUBMED:	32213539
PROVIDER:	scopus
PMCID:	PMC7196485
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083861112&doi=10.1158%2f2159-8290.CD-20-0215&partnerID=40&md5=92cee13c97fd04bcfc757954a1f22dcc
Notes:	Clare J. Wilhelm's name is misspelled on the original publication -- Article -- Source: Scopus