Targeting her3, a catalytically defective receptor tyrosine kinase, prevents resistance of lung cancer to a third-generation egfr kinase inhibitor

Donatella Romaniello, Ilaria Marrocco, Nishanth Belugali Nataraj, Irene Ferrer, Diana Drago-Garcia, Itay Vaknin, Roni Oren, Moshit Lindzen, Soma Ghosh, Matthew Kreitman, Jeanette Clarissa Kittel, Nadege Gaborit, Gretchen Bergado Baez, Belinda Sanchez, Raya Eilam, Eli Pikarsky, Luis Paz-Ares, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.

Original languageAmerican English
Article number2394
Pages (from-to)1-20
Number of pages20
Issue number9
StatePublished - Sep 2020

Bibliographical note

Funding Information:
Funding: D.R. and I.M. thank the Lombroso Foundation for fellowships. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the European Research Council (Oncombine; Grant #740469) and the Dr. Miriam and Sheldon Adelson Medical Research Foundation (Grant #15).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.


  • Drug resistance
  • EGFR
  • Kinase inhibitor
  • Lung cancer
  • Monoclonal antibody
  • Osimertinib


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