Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling.
Birgit WildingDirk ScharnDietrich BöseAnke BaumValeria SantoroPaolo ChettaRenate SchnitzerDana A BotesteanuChristoph ReiserStefan KorniggPetr KneslAlexandra HörmannAnna KöferleMaja CorcokovicSimone LiebGuido ScholzJens BruchhausMarkus SpinaJosef BallaBiljana Peric-SimovJasmin ZimmerSophie MitznerThomas N FettAlexandra BeranLyne LamarreThomas GerstbergerDaniel GerlachMarkus BauerAndreas BergnerAndreas SchlattlGerd BaderMatthias TreuHarald EngelhardtStephan ZahnJulian E FuchsJohannes ZuberPeter EttmayerMark PearsonMark PetronczkiNorbert KrautDarryl B McConnellFlavio SolcaRalph A NeumullerPublished in: Nature cancer (2022)
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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- wild type
- advanced non small cell lung cancer
- small molecule
- endothelial cells
- small cell lung cancer
- high throughput
- copy number
- oxidative stress
- genome wide
- signaling pathway
- stem cells
- transcription factor
- gene expression
- induced pluripotent stem cells
- anti inflammatory
- chronic myeloid leukemia
- cell therapy
- minimally invasive
- newly diagnosed