Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

Baldassarre, Tomas; Truesdell, Peter; Craig, Andrew W.B.

doi:10.1186/s13058-017-0900-z

Cited by 39 publications

(27 citation statements)

References 52 publications

(75 reference statements)

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“…The treatments with Myc B or Trastuzumab also suppressed metastasis in our HER2+ tumor models. This is consistent with HER2 signaling-driven cell motility being sensitive to Trastuzumab 47 , and the actin cytoskeleton reorganization being sensitive to Myc B (this study). Overall, combination therapies targeting both HER2 and actin polymerization may allow for comprehensive elimination of HER2+ tumors and metastases.…”

Section: Discussionsupporting

confidence: 89%

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis

Nersesian

Williams

Newsted

et al. 2018

Sci Rep

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Amplification of HER2 leads to development of HER2-positive (HER2+) cancers with high rates of metastasis compared to other cancer subtypes. The goal of this study was to probe the vulnerability of HER2+ cancer cells to a filamentous actin (F-actin) severing and capping toxin. The growth and viability of human HER2+ breast cancer (HCC1954) and ovarian cancer (SKOV3) cell lines were significantly impaired upon treatment with the marine macrolide mycalolide B (Myc B) at doses above 100 nanomolar. Further testing of Myc B in combination with the antibody-drug conjugate Trastuzumab-emtansine (T-DM1) led to improved killing of SKOV3 cells compared to either treatment alone. At sub-lethal doses, treatment of HER2+ cancer cells with Myc B resulted in rapid loss of leading edge protrusions and formation of aggresomes containing F-actin and the actin regulatory protein Cortactin. This correlated with robust inhibition of HER2+ cancer cell motility and invasion with Myc B treatment. In SKOV3 tumor xenograft assays, intratumoral injections of Myc B impaired HER2+ tumor growth and metastasis, with maximal effects observed in combination with systemic delivery of Trastuzumab. Metastasis of SKOV3 cells to the lungs following tail vein injection was also reduced by Myc B. Together, these findings provide rationale for targeting F-actin in combination with existing therapies for HER2+ cancers to reduce metastasis.

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Section: Discussionsupporting

confidence: 89%

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis

Nersesian

Williams

Newsted

et al. 2018

Sci Rep

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“…This is similar to at least one mode of action of the clinical grade HER2 inhibitory antibody Trastuzumab, that promotes internalization of HER2 in HER2-positive EOC cancer cells. 24 However, further studies are needed to map the TGFBR2 epitopes of these lead inhibitory antibodies, and fully dissect their potential modes of action.…”

Section: Discussionmentioning

confidence: 99%

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

et al. 2018

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Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models, OncoImmunology, 8:2, e1539613, ABSTRACT Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models. ARTICLE HISTORY

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“…In other cancers, such as Human epidermal growth factor receptor 2 (HER2)-positive tumors, Endophilin levels are elevated [136]. Endophilin knock-down reduced HER2 uptake and elevated the levels of HER2 at the plasma membrane.…”

Section: Is Feme Involved In Neurodegenerative Diseases?mentioning

confidence: 99%

“…This decreased AKT and ERK downstream signaling as well as migration and metastasis of HER2+ cancer cells. Interestingly, elevated HER2 levels at the cell surface upon Endophilin depletion made cells more sensitive to trastuzumab and trastuzumab-emtansine (T-DM1) antibody therapies [136]. As several receptors, including EGFR, accumulate at the cell surface upon FEME inhibition [16], the possibility that blocking the pathway may potentiate anti-cancer therapies is exciting.…”

Section: Is Feme Involved In Neurodegenerative Diseases?mentioning

confidence: 99%

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

Casamento

Boucrot

2020

Biochemical Journal

108

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Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Clathrin-mediated endocytosis (CME) is the housekeeping pathway in resting cells but additional Clathrin-independent endocytic (CIE) routes, including Fast Endophilin-Mediated Endocytosis (FEME), internalize specific cargoes and support diverse cellular functions. FEME is part of the Dynamin-dependent subgroup of CIE pathways. Here, we review our current understanding of the molecular mechanism of FEME. Key steps are: (i) priming, (ii) cargo selection, (iii) membrane curvature and carrier formation, (iv) membrane scission and (v) cytosolic transport. All steps are controlled by regulatory mechanisms mediated by phosphoinositides and by kinases such as Src, LRRK2, Cdk5 and GSK3β. A key feature of FEME is that it is not constitutively active but triggered upon the stimulation of selected cell surface receptors by their ligands. In resting cells, there is a priming cycle that concentrates Endophilin into clusters on discrete locations of the plasma membrane. In the absence of receptor activation, the patches quickly abort and new cycles are initiated nearby, constantly priming the plasma membrane for FEME. Upon activation, receptors are swiftly sorted into pre-existing Endophilin clusters, which then bud to form FEME carriers within 10 s. We summarize the hallmarks of FEME and the techniques and assays required to identify it. Next, we review similarities and differences with other CIE pathways and proposed cargoes that may use FEME to enter cells. Finally, we submit pending questions and future milestones and discuss the exciting perspectives that targeting FEME may boost treatments against cancer and neurodegenerative diseases.

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Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

Cited by 39 publications

References 52 publications

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

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