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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2020 Jan 25

PMID 31978326

Citations 28

Authors

Dhivya R Sudhan

Angel Guerrero-Zotano

Helen Won

Paula Gonzalez 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 Jr

Alshad S Lalani

Richard Bryce

Alan Auerbach

Ariella B Hanker

Carlos L Arteaga

Affiliations

Soon will be listed here.

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.

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