Abstract
ErbB2 overexpression identifies a subclass of breast cancer as ErbB2-positive that is frequently associated with poor prognosis. Current ErbB2-targeted therapies have profoundly improved patient outcomes, but mutations occurring in ErbB2 have been shown to confer drug resistance. Induction of ErbB2 degradation was proposed as an intriguing strategy to battle with ErbB2-positive breast cancer and reduced mutation-incurred drug resistance. Although multiple HSP90 inhibitors have been demonstrated to effectively trigger ErbB2 degradation, none succeeded in the clinical evaluations. To develop novel ErbB2-targeting strategies, we investigated the endocytic degradation and reversible ubiquitylation of ErbB2 in breast cancer. In this study, we reveal that HSP90 inhibition leads to efficient ubiquitylation and endocytic degradation of ErbB2 through the canonical endo-lysosomal route. USP2 associates with internalized ErbB2 and prevents its lysosomal sorting and degradation via exerting deubiquitylase activity. Accordingly, the USP2 inhibitor ML364 is capable of inducing ErbB2 ubiquitylation and accelerating its turnover. ML364 potentiates the pro-degradation effects of HSP90 inhibitors on ErbB2 and hence sensitizes ErbB2-positive breast cancer cells to HSP90 inhibition. The combination of USP2 and HSP90 inhibitors effectively restrains ErbB2-positive breast cancer xenograft growth in vivo. Based on these observations, we conclude that USP2 safeguards ErbB2 surface levels by antagonizing its ubiquitylation-mediated endocytic degradation, which can be exploited to design novel therapeutic strategies against ErbB2-driven malignancies as combinatorial treatment with HSP90 inhibitors.
Highlights
Receptor tyrosine kinases (RTK) comprise a group of transmembrane proteins that transmit extracellular signals to regulate a diverse array of intracellular signaling circuitries, which have been associated with essential events during development, adult homeostasis, and human diseases [1]
The destabilization and subsequent degradation of ErbB2 are achieved by displacing HSP90 that chaperones ErbB2 conformation with HSP70 that leads to ErbB2 ubiquitylation through recruiting the ubiquitin ligase CHIP (C-terminal Hsc70-Interacting Protein), which process is enabled by various HSP90 inhibitors [11,12,13]
Since the observation of geldanamycin-incurred ErbB2 degradation, different intracellular itineraries and degradation pathways for ubiquitylated ErbB2 have been proposed in ErbB2-positive breast cancer cells exposed to HSP90 inhibitors [11, 21,22,23,24]
Summary
Receptor tyrosine kinases (RTK) comprise a group of transmembrane proteins that transmit extracellular signals to regulate a diverse array of intracellular signaling circuitries, which have been associated with essential events during development, adult homeostasis, and human diseases [1]. The ErbB family of RTK has been closely associated with the development and progression of a number of malignancies, with two members EGFR and ErbB2 already proved as efficient therapeutic targets that received FDA approvals [2,3,4]. ErbB2 targeting has proved an effective approach in the battle against ErbB2positive breast cancers, and current therapies approved by. The seemingly unavoidable resistance to the therapeutic agents against ErbB2 was acquired by cancer cells in most cases through diverse mechanisms, which include mutations occurring in ErbB2 that abrogate antibody or inhibitor binding [6,7,8]. It is conceivable that this strategy will likely eliminate resistance incurred by ErbB2 mutations, as preceding investigations already revealed effectiveness of this approach against trastuzumab-resistant breast cancer [10]. Initial clinical trials with the HSP90 inhibitors tanespimycin (17-AAG) and alvespimycin (17DMAG), two derivatives of the antibiotic geldanamycin, provided additional lines of evidence that supports the validity of targeting HSP90 in ErbB2-positive breast cancers [16, 17]
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