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
    263 Makker
  2. Gary Ulaner
    146 Ulaner
  3. Neal Rosen
    425 Rosen
  4. David Solit
    779 Solit
  5. Ronglai Shen
    204 Shen
  6. Helena Alexandra Yu
    281 Yu
  7. David Hyman
    354 Hyman
  8. Alan Loh Ho
    238 Ho
  9. Jason S Lewis
    456 Lewis
  10. Michael Forman Berger
    765 Berger
  11. Maria Eugenia Arcila
    657 Arcila
  12. Mark Kris
    869 Kris
  13. Maurizio Scaltriti
    169 Scaltriti
  14. Charles Rudin
    489 Rudin
  15. Pedram Razavi
    172 Razavi
  16. David Randolph Jones
    417 Jones
  17. John Thomas Poirier
    82 Poirier
  18. Bob Tingkan Li
    278 Li
  19. Inna   Khodos
    36 Khodos
  20. Marissa   Mattar
    57 Mattar
  21. James Michael Isbell
    127 Isbell
  22. Emiliano Cocco
    31 Cocco
  23. Michael David Offin
    170 Offin
  24. Besnik Qeriqi
    15 Qeriqi
  25. Sandra Misale
    17 Misale
  26. Yanyan Cai
    15 Cai
  27. Sophie Shifman
    10 Shifman
  28. Chongrui Xu
    8 Xu
  29. Mackenzie Myers
    15 Myers
  30. Hai-Yan Tu
    7 Tu
  31. Megan Little
    5 Little
  32. Clare Jon Wilhelm
    25 Wilhelm