Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : ckbsupport@jax.org
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. |
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 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 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 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 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 |
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 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 | 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 |