MiR-205 as predictive biomarker and adjuvant therapeutic tool in combination with trastuzumab

// Alessandra Cataldo 1 , Claudia Piovan 1 , Ilaria Plantamura 1 , Elvira D’Ippolito 1 , Simone Camelliti 1 , Patrizia Casalini 2 , Marta Giussani 2 , Olivier Deas 3 , Stefano Cairo 3 , Jean-Gabriel Judde 3 , Elda Tagliabue 2 and Marilena V. Iorio 1 1 Start Up Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Molecular Targeting Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Xentech, Genopole Campus 3, Evry, Paris Correspondence to: Marilena V. Iorio, email: marilena.iorio@istitutotumori.mi.it 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 ABSTRACT 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.