2. Academic Validation
  3. A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer

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

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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