Shed HER2 extracellular domain in HER2‐mediated tumor growth and in trastuzumab susceptibility

Ghedini, Gaia C.; Ciravolo, Valentina; Tortoreto, Monica; Giuffré, Sarah; Bianchi, Francesca; Campiglio, Manuela; Mortarino, Mimosa; Figini, Mariangela; Coliva, Angela; Carcangiu, Maria Luisa; Zambetti, Milvia; Piazza, Tiziana; Ferrini, Silvano; Ménard, Sylvie; Tagliabue, Elda; Pupa, Serenella M.

doi:10.1002/jcp.22257

Cited by 29 publications

(29 citation statements)

References 40 publications

(63 reference statements)

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“…Many other membrane-anchored proteins release their ECD through proteolytic cleavage, such as HER2 and EGFR (28,29). However, clinical significance of such form has been difficult to establish, and effect on response to targeted therapy has not been fully elucidated (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Challita-Eid¹,

Satpayev²,

Yang³

et al. 2016

Cancer Research

414

386

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The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Challita-Eid¹,

Satpayev²,

Yang³

et al. 2016

Cancer Research

414

386

View full text Add to dashboard Cite

show abstract

“…injections of 4 mg/kg trastuzumab or diluent NaCl solution (0.9%). The use of the two different dosing schedules of trastuzumab administration is based on the reliable results we previously obtained (21,22). Tumors were calibrated twice weekly and tumor volume was calculated as above.…”

Section: Tg Mice and In Vivo Therapymentioning

confidence: 99%

Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab

et al. 2014

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A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment. Cancer Res; 74(21); 6248-59. Ó2014 AACR.

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“…Furthermore, soluble HER2 ectodomain has been shown to inhibit signaling (33). For other RTKs including HER4 and MET, shedding likely reduces RTK signaling at the cell surface (34,35).…”

Section: Implications Of Rtk Ectodomain Shedding In Modulating Drugmentioning

confidence: 99%

ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling

Miller¹,

Meyer²,

Beste

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM "sheddase" function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor-driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.cell signaling networks | metalloproteinase activity | cue-signal-response analysis | amphiregulin

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Shed HER2 extracellular domain in HER2‐mediated tumor growth and in trastuzumab susceptibility

Cited by 29 publications

References 40 publications

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab

ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling

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