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

Cancer Cell. 2020 Feb 10;37(2):183-199.e5. doi: 10.1016/j.ccell.2019.12.013. Epub 2020 Jan 23.

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.

Keywords: HER2 mutations; TORC1; drug resistance; neratinib; precision oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / drug effects
  • Mechanistic Target of Rapamycin Complex 1 / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Quinolines / pharmacology*
  • Receptor, ErbB-2 / drug effects
  • Receptor, ErbB-2 / genetics
  • Signal Transduction / drug effects

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • Receptor, ErbB-2
  • Mechanistic Target of Rapamycin Complex 1
  • neratinib