Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
27
07
2021
accepted:
16
06
2022
entrez:
26
7
2022
pubmed:
27
7
2022
medline:
29
7
2022
Statut:
ppublish
Résumé
Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.
Identifiants
pubmed: 35883003
doi: 10.1038/s43018-022-00412-y
pii: 10.1038/s43018-022-00412-y
doi:
Substances chimiques
Protein Kinase Inhibitors
0
EGFR protein, human
EC 2.7.10.1
ERBB2 protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
821-836Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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