Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status

// Luigi Formisano 1 , Valentina D'Amato 1 , Alberto Servetto 1 , Simona Brillante 1 , Lucia Raimondo 1 , Concetta Di Mauro 1 , Roberta Marciano 1 , Roberta Clara Orsini 1 , Sandro Cosconati 2 , Antonio Randazzo 3 , Sarah J. Parsons 4 , Nunzia Montuori 5 , Bianca Maria Veneziani 6 , Sabino De Placido 1 , Roberta Rosa 1, * , Roberto Bianco 1, * 1 Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy 2 DiSTABiF, Second University of Naples, Caserta, Italy 3 Department of Pharmacy, University of Naples “Federico II”, Naples, Italy 4 Department of Microbiology, Immunology & Cancer Biology, Cancer Center, University of Virginia Health System, Charlottesville, Virginia, USA 5 Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy 6 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy * These authors have contributed equally to this work Correspondence to: Roberto Bianco, e-mail: robianco@unina.it Keywords: Src, NSCLC, EGFR inhibitors, MEK inhibitors, drug resistance Received: March 04, 2015      Accepted: July 23, 2015      Published: August 03, 2015 ABSTRACT Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib. Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.