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Ref Type Journal Article
PMID (31978326)
Authors Sudhan DR, Guerrero-Zotano A, Won H, González Ericsson P, Servetto A, Huerta-Rosario M, Ye D, Lee KM, Formisano L, Guo Y, Liu Q, Kinch LN, Red Brewer M, Dugger T, Koch J, Wick MJ, Cutler RE, Lalani AS, Bryce R, Auerbach A, Hanker AB, Arteaga CL
Title Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.
Journal Cancer cell
Vol
Issue
Date 2020 Jan 23
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 V777L PIK3CA H1047R breast cancer resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring ERBB2 (HER2) V777L and PIK3CA H1047R demonstrated resistance to Nerlynx (neratinib) in culture (PMID: 31978326). 31978326
ERBB2 L755S PIK3CA H1047R breast cancer resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring ERBB2 (HER2) L755S and PIK3CA H1047R demonstrated resistance to Nerlynx (neratinib) in culture (PMID: 31978326). 31978326
ERBB2 V777L PIK3CA H1047R breast cancer sensitive Everolimus + Neratinib Preclinical - Cell culture Actionable In a preclinical study, Afinitor (everolimus) and Nerlynx (neratinib) worked synergistically to inhibit viability of a breast cancer cell line harboring ERBB2 (HER2) V777L and PIK3CA H1047R in culture (PMID: 31978326). 31978326
ERBB2 mut PIK3CA mut breast cancer predicted - resistant Neratinib Case Reports/Case Series Actionable In a Phase II trial (SUMMIT), 6 of 7 patients with ERBB2 (HER2)-mutant breast cancer who progressed on Nerlynx (neratinib) harbored either a PIK3CA (n=5) or PIK3R1 (n=1) mutation (PMID: 31978326). 31978326
ERBB2 G778_P780dup PIK3CA H1047R breast cancer decreased response Neratinib Preclinical - Pdx Actionable In a preclinical study, Nerlynx (neratinib) resulted in a moderate delay of tumor growth in a breast cancer patient-derived xenograft model harboring ERBB2 (HER2) G778_P780dup and PIK3CA H1074R (PMID: 31978326). 31978326
ERBB2 G776V PIK3CA H1047R ovarian cancer sensitive Everolimus + Neratinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Afinitor (everolimus) to treatment with Nerlynx (neratinib) inhibited viability of an ovarian cancer cell line harboring ERBB2 (HER2) G776V and expressing PIK3CA H1047R in culture (PMID: 31978326). 31978326
ERBB2 G776V PIK3CA H1047R ovarian cancer resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, expression of PIK3CA H1047R conferred resistance to Nerlynx (neratinib) in an ovarian cancer cell line harboring ERBB2 (HER2) G776V in culture (PMID: 31978326). 31978326
ERBB2 L755S PIK3CA H1047R breast cancer sensitive Everolimus + Neratinib Preclinical - Cell culture Actionable In a preclinical study, Afinitor (everolimus) and Nerlynx (neratinib) worked synergistically to inhibit viability of a breast cancer cell line harboring ERBB2 (HER2) L755S and PIK3CA H1047R in culture (PMID: 31978326). 31978326