The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15–20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scafold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enhancing tumorigenesis. Therefore, inhibiting p130Cas/ErbB2 interaction might represent a new therapeutic strategy to target breast cancer. Here we demonstrate by performing Molecular Modeling, Molecular Dynamics, dot blot, ELISA and fuorescence quenching experiments, that p130Cas binds directly to ErbB2. Then, by structure-based virtual screening, we identifed two potential inhibitors of p130Cas/ErbB2 interaction. Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ ErbB2 binding and signifcantly afect cell proliferation and sensitivity to Trastuzumab. Overall, this study identifes p130Cas/ErbB2 complex as a potential breast cancer target revealing new therapeutic perspectives for protein-protein interaction (PPI).

Modeling ErbB2-p130Cas interaction to design new potential anticancer agents.

Andrea Costamagna;Matteo Rossi Sebastiano;Dora Natalini;Giorgio Valabrega;Paola Defilippi;Sonja Visentin;Giuseppe Ermondi;Emilia Turco;Giulia Caron
Co-last
;
Sara Cabodi
Co-last
2019

Abstract

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15–20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scafold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enhancing tumorigenesis. Therefore, inhibiting p130Cas/ErbB2 interaction might represent a new therapeutic strategy to target breast cancer. Here we demonstrate by performing Molecular Modeling, Molecular Dynamics, dot blot, ELISA and fuorescence quenching experiments, that p130Cas binds directly to ErbB2. Then, by structure-based virtual screening, we identifed two potential inhibitors of p130Cas/ErbB2 interaction. Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ ErbB2 binding and signifcantly afect cell proliferation and sensitivity to Trastuzumab. Overall, this study identifes p130Cas/ErbB2 complex as a potential breast cancer target revealing new therapeutic perspectives for protein-protein interaction (PPI).
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Andrea Costamagna, Matteo Rossi Sebastiano, Dora Natalini, Matilde Simoni, Giorgio Valabrega, Paola Defilippi, Sonja Visentin, Giuseppe Ermondi, Emilia Turco, Giulia Caron, Sara Cabodi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1694155
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