@article{ff63e97a5d9243a7935487388b4e2249,
title = "Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers",
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",
author = "Sudhan, {Dhivya R} and Angel Guerrero-Zotano and Helen Won and {Gonz{\'a}lez Ericsson}, Paula and Alberto Servetto and Mariela Huerta-Rosario and Dan Ye and Lee, {Kyung min} and Luigi Formisano and Yan Guo and Qi Liu and Kinch, {Lisa N.} and {Red Brewer}, Monica and Teresa Dugger and James Koch and Wick, {Michael J.} and Cutler, {Richard E.} and Lalani, {Alshad S.} and Richard Bryce and Alan Auerbach and Hanker, {Ariella B.} and Arteaga, {Carlos L.}",
note = "Funding Information: This study was supported by UTSW Simmons Cancer Center P30 CA142543 , CPRIT RR170061 (C.L.A.), NCI Breast SPORE P50 CA098131 , Vanderbilt-Ingram Cancer Center P30 CA68485 , Susan G. Komen Breast Cancer Foundation SAC100013 (C.L.A.), Breast Cancer Research Foundation (C.L.A.), NCI R01CA224899 (C.L.A. and A.B.H.), and Susan G. Komen Postdoctoral Fellowship PDF17487926 (K.M.L.). We acknowledge the assistance of the UTSW Tissue Resource, supported in part by NCI 5P30CA142543 . Funding Information: R.E.C., A.S.L., R.B., and A.A. are employees and shareholders of Puma Biotechnology, Inc. A.G.Z. has received research and travel grants from Pfizer . A.B.H. receives research grant support from Takeda and has received a travel grant from Puma Biotechnology, Inc. C.L.A receives or has received research grants from Puma Biotechnology , Pfizer , Lilly , Bayer , Takeda , and Radius ; holds stock options in Provista and Y-TRAP; serves or has served in an advisory role to Novartis, Merck, Lilly, Symphogen, Daiichi Sankyo, Radius, Taiho Oncology, H3Biomedicine, OrigiMed, Puma Biotechnology, and Sanofi; and reports scientific advisory board remuneration from the Komen Foundation. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = feb,
day = "10",
doi = "10.1016/j.ccell.2019.12.013",
language = "English (US)",
volume = "37",
pages = "183--199.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}