2. Academic Validation
  3. Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

  • Nat Cancer. 2022 Jul;3(7):821-836. doi: 10.1038/s43018-022-00412-y.
Birgit Wilding 1,  Dirk Scharn 2,  Dietrich Böse 2,  Anke Baum 2,  Valeria Santoro 2,  Paolo Chetta 2,  Renate Schnitzer 2,  Dana A Botesteanu 2,  Christoph Reiser 2,  Stefan Kornigg 2,  Petr Knesl 2,  Alexandra Hörmann 2,  Anna Köferle 2,  Maja Corcokovic 2,  Simone Lieb 2,  Guido Scholz 2,  Jens Bruchhaus 2,  Markus Spina 2,  Josef Balla 2,  Biljana Peric-Simov 2,  Jasmin Zimmer 2,  Sophie Mitzner 2,  Thomas N Fett 2,  Alexandra Beran 2,  Lyne Lamarre 2,  Thomas Gerstberger 2,  Daniel Gerlach 2,  Markus Bauer 2,  Andreas Bergner 2,  Andreas Schlattl 2,  Gerd Bader 2,  Matthias Treu 2,  Harald Engelhardt 2,  Stephan Zahn 2,  Julian E Fuchs 2,  Johannes Zuber 3 4,  Peter Ettmayer 2,  Mark Pearson 2,  Mark Petronczki 2,  Norbert Kraut 2,  Darryl B McConnell 2,  Flavio Solca 5,  Ralph A Neumüller 6
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV, Vienna, Austria. birgit.wilding@boehringer-ingelheim.com.
  • 2 Boehringer Ingelheim RCV, Vienna, Austria.
  • 3 Institute of Molecular Pathology (IMP), Vienna, Austria.
  • 4 Medical University of Vienna, Vienna, Austria.
  • 5 Boehringer Ingelheim RCV, Vienna, Austria. flavio.solca@boehringer-ingelheim.com.
  • 6 Boehringer Ingelheim RCV, Vienna, Austria. ralph.neumueller@boehringer-ingelheim.com.
PMID: 35883003 DOI: 10.1038/s43018-022-00412-y
Abstract

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.

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