MiR-205 as predictive biomarker and adjuvant therapeutic tool in combination with trastuzumab
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Alessandra Cataldo1, Claudia Piovan1, Ilaria Plantamura1, Elvira D’Ippolito1, Simone Camelliti1, Patrizia Casalini2, Marta Giussani2, Olivier Déas3, Stefano Cairo3, Jean-Gabriel Judde3, Elda Tagliabue2 and Marilena V. Iorio1
1Start Up Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Molecular Targeting Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Xentech, Genopole Campus 3, Evry, Paris
Marilena V. Iorio, email: [email protected]
Keywords: microRNA; breast cancer; HER2-3; trastuzumab; biomarkers
Abbreviations: BC: breast cancer; TKI: tyrosin kinase inhibitor; PR: pathological response; PDX: patient-derived xenograft
Received: December 30, 2017 Accepted: February 25, 2018 Published: June 15, 2018
Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it significantly improved their clinical outcome, 50% of them do not benefit from this drug and disease recurs, underlining the need of reliable predictive biomarkers and new therapeutic strategies. Strikingly, despite all the molecular analyses performed to identify the escape mechanisms behind this resistance, it still represents a question point. MiRNAs have been correlated with occurrence and progression of human cancer, and their potential as clinical tools has emerged in the last years. We previously reported that oncosuppressive miR-205 targets HER3, thus increasing the responsiveness to TKIs lapatinib and gefitinib in preclinical models.
Here we demonstrate that HER3 inhibition by miR-205 ectopic expression or siRNA-mediated silencing improves the responsiveness to Trastuzumab in vitro in HER2+ BC cell lines, and that this effect is exerted through impairment of AKT-mediated pathway. Moreover, evaluating a series of 52 HER2+ BC patients treated with adjuvant Trastuzumab, we observed that higher miR-205 expression is significantly associated with better outcome (disease-free survival).
In summary, our data indicate that miR-205 could predict Trastuzumab efficacy and that its modulation might be useful as adjuvant treatment to improve the response to the drug.
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