| Literature DB >> 31978326 |
Dhivya R Sudhan1, Angel Guerrero-Zotano2, Helen Won3, Paula González Ericsson4, Alberto Servetto1, Mariela Huerta-Rosario1, Dan Ye1, Kyung-Min Lee1, Luigi Formisano2, Yan Guo5, Qi Liu6, Lisa N Kinch7, Monica Red Brewer2, Teresa Dugger2, James Koch2, Michael J Wick8, Richard E Cutler9, Alshad S Lalani9, Richard Bryce9, Alan Auerbach9, Ariella B Hanker10, Carlos L Arteaga11.
Abstract
We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.Entities:
Keywords: HER2 mutations; TORC1; drug resistance; neratinib; precision oncology
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Year: 2020 PMID： 31978326 PMCID： PMC7301608 DOI： 10.1016/j.ccell.2019.12.013
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743