A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer

  • Cancer Res. 2022 Apr 15;82(8):1633-1645. doi: 10.1158/0008-5472.CAN-21-2693.
Jieun Son  1  2  3 ,  Jaebong Jang  #  4  5 ,  Tyler S Beyett  #  4  5 ,  Yoonji Eum  1  2  3 ,  Heidi M Haikala  1  2  3 ,  Alyssa Verano  4  5 ,  Mika Lin  1  2  3 ,  John M Hatcher  4  5 ,  Nicholas P Kwiatkowski  4  5 ,  Pinar Ö Eser  1  2  3 ,  Michael J Poitras  6 ,  Stephen Wang  7 ,  Man Xu  7 ,  Prafulla C Gokhale  6  7 ,  Michael D Cameron  8 ,  Michael J Eck  4  5 ,  Nathanael S Gray  9 ,  Pasi A Jänne  1  2  3  7
Affiliations
  • 1. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 6. Experimental Therapeutics Core, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 7. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 8. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida.
  • 9. Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, California.
  • # Contributed equally.
PMID: 35149586 DOI: 10.1158/0008-5472.CAN-21-2693
Abstract

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung Cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with Other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.

Significance: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung Cancer.

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