ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.

Autor:	McKernan CM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA., Khatri A; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA., Hannigan M; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA., Child J; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA., Chen Q; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA., Mayro B; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA., Snyder D; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA., Nicchitta CV; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA., Pendergast AM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: ann.pendergast@duke.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Aug 30; Vol. 40 (9), pp. 111268.
DOI:	10.1016/j.celrep.2022.111268
Abstrakt:	Patients with human epidermal growth factor receptor 2-positive (HER2+/ERBB2) breast cancer often present with brain metastasis. HER2-targeted therapies have not been successful to treat brain metastases in part due to poor blood-brain barrier (BBB) penetrance and emergence of resistance. Here, we report that Abelson (ABL) kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinases phosphorylate the RNA-binding protein Y-box-binding protein 1 (YB-1). ABL kinase inhibition disrupts binding of YB-1 to the ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. ABL-dependent tyrosine phosphorylation of YB-1 promotes HER2 translation. Notably, loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a therapeutic target for HER2+ brain metastasis patients. Competing Interests: Declaration of interests A.M.P. is a consultant and advisory board member for the Pew Charitable Trusts. C.M.M. is an employee of Altavant Sciences. M.H. is an employee of Torque Bio, Inc. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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