Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability

Sweeney, William E.; Hamahira, Kiyoshi; Sweeney, Jennifer; Garcia-Gatrell, Michelle; Frost, Philip; Avner, Ellis D.

doi:10.1046/j.1523-1755.2003.00232.x

Cited by 74 publications

(62 citation statements)

References 42 publications

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“…EGFR overexpression, mislocalization, and activation have been reported in human ADPKD and rodent models. 57 Treatment with EGFR tyrosine kinase inhibitors inhibits renal cyst growth in several PKD rodent models, 58,59 but not all. 60 The EGFR and Src interact with each other, Src can phosphorylate multiple tyrosine residues of the EGFR, and both kinases are thought to be able to mutually activate each other.…”

Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Srcdependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/ STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR-or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

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Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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“…13,40,41 Affected animals die at PN24 (average) with a range of PN21 to PN29. Extrarenal manifestations include biliary proliferation and BDE.…”

Section: Bpk Modelmentioning

confidence: 99%

“…13,24 Figure 5 compares the effectiveness of Src inhibition (SKI-606) on EGFR activity with published EGFR targeted therapies. Figure 5A, lanes 2 through 5, demonstrates the increased levels of total EGFR in BPK kidneys compared with Balb/C kidneys ( Figure 5A, lane 1).…”

Section: Comparison Of Targeted Therapies On Active Egfr (Erbb1) In Bpkmentioning

confidence: 99%

“…Tissue lysates were then extracted in fresh RIPAϩ as described previously 13 and were adjusted to an equal amount of protein (3.5 to 5 mg; determined by BCA assay; Pierce, Rockford, IL) and equal volume.…”

Section: Immunoprecipitation and Western Analysismentioning

confidence: 99%

“…12 Previous work in our laboratory demonstrated that the combination of therapies inhibiting EGF receptor (EGFR) autophosphorylation in addition to decreasing EGFR ligand availability provide a novel example of effective combination therapy in murine PKD. 13 Extending this concept, we reasoned that identification of signaling intermediates that regulate multiple steps in a single pathophysiologic pathway in addition to acting as an integration point for multiple signaling cascades may provide even greater benefit than EGFR combination therapy. Analysis of multiple pathways implicated in PKD and the potential cross-talk of these pathways allowed us to identify intermediate signaling molecules that could provide such potential therapeutic targets.…”

mentioning

confidence: 99%

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Src Inhibition Ameliorates Polycystic Kidney Disease

Sweeney¹,

Vigier²,

Frost³

et al. 2008

Journal of the American Society of Nephrology

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150

128

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Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60 c-Src ) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Srcmediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.

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Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Castro-Suárez

Rodríguez-Vera

Villegas

et al. 2019

The Journal of Clinical Pharma

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression and mislocalization of epidermal growth factor receptor (EGFR) to the apical membranes of cystic epithelial cells. Nimotuzumab is a humanized antibody that recognizes an extracellular domain III of human EGFR. The aim of this study was to assess the pharmacokinetic behavior of nimotuzumab in patients with ADPKD given as a single dose. A phase I, single‐center, and noncontrolled open clinical study was conducted. Five patients were enrolled at each of the following fixed‐dose levels: 50, 100, 200, and 400 mg. Intravenous continuous infusions of nimotuzumab were administered every 14 days during a year, except the first administration, when blood samples were drawn during 28 days for pharmacokinetic assessments. Subjects were closely monitored during the trial and at completion of the administration of nimotuzumab, including the anti‐idiotypic response. For the first time, nimotuzumab was used for treating a nononcological disease. The administration of nimotuzumab showed dose‐dependent kinetics. Nimotuzumab does not develop anti‐idiotypic response against the murine portion present in the hypervariable region of the antibody present in the serum of the patients treated. No significant differences were found in the systemic clearance between the 100‐ and 400‐mg dose, which indicates that the optimal biological dose is in this range of dose.

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Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability

Cited by 74 publications

References 42 publications

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Src Inhibition Ameliorates Polycystic Kidney Disease

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

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