Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers

Dhivya R. Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N. Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J. Wick, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan AuerbachAriella B. Hanker, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)183-199.e5
JournalCancer Cell
Volume37
Issue number2
DOIs
StatePublished - Feb 10 2020

Keywords

  • HER2 mutations
  • TORC1
  • drug resistance
  • neratinib
  • precision oncology

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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