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

Autor:	Sudhan DR; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Guerrero-Zotano A; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Won H; Memorial Sloan Kettering Cancer Center, New York, NY, USA., González Ericsson P; Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA., Servetto A; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Huerta-Rosario M; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ye D; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Lee KM; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Formisano L; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Guo Y; Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA., Liu Q; Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA., Kinch LN; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Red Brewer M; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Dugger T; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Koch J; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Wick MJ; START, 4383 Medical Drive, San Antonio, TX, USA., Cutler RE Jr; Puma Biotechnology, Inc., Los Angeles, CA, USA., Lalani AS; Puma Biotechnology, Inc., Los Angeles, CA, USA., Bryce R; Puma Biotechnology, Inc., Los Angeles, CA, USA., Auerbach A; Puma Biotechnology, Inc., Los Angeles, CA, USA., Hanker AB; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: ariella.hanker@utsouthwestern.edu., Arteaga CL; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: carlos.arteaga@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2020 Feb 10; Vol. 37 (2), pp. 183-199.e5. Date of Electronic Publication: 2020 Jan 23.
DOI:	10.1016/j.ccell.2019.12.013
Abstrakt:	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. Competing Interests: Declaration of Interests 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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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