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:
Notes: Clare J. Wilhelm's name is misspelled on the original publication -- Article -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    108 Makker
  2. Gary Ulaner
    114 Ulaner
  3. Neal Rosen
    381 Rosen
  4. David Solit
    546 Solit
  5. Ronglai Shen
    143 Shen
  6. Helena Alexandra Yu
    133 Yu
  7. David Hyman
    302 Hyman
  8. Alan Loh Ho
    120 Ho
  9. Jason S Lewis
    305 Lewis
  10. Michael Forman Berger
    497 Berger
  11. Maria Eugenia Arcila
    459 Arcila
  12. Mark Kris
    714 Kris
  13. Jorge Sergio Reis
    382 Reis
  14. Maurizio Scaltriti
    125 Scaltriti
  15. Charles Rudin
    229 Rudin
  16. Pedram Razavi
    61 Razavi
  17. David Randolph Jones
    198 Jones
  18. John Thomas Poirier
    72 Poirier
  19. Bob Tingkan Li
    99 Li
  20. Inna   Khodos
    11 Khodos
  21. Marissa   Mattar
    19 Mattar
  22. James Michael Isbell
    46 Isbell
  23. Emiliano Cocco
    22 Cocco
  24. Michael David Offin
    44 Offin
  25. Besnik Qeriqi
    8 Qeriqi
  26. Sandra Misale
    7 Misale
  27. Yanyan Cai
    7 Cai
  28. Chongrui Xu
    5 Xu
  29. Mackenzie Myers
    11 Myers
  30. Hai-Yan Tu
    2 Tu
  31. Megan Little
    1 Little