Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status
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Luigi Formisano1, Valentina D'Amato1, Alberto Servetto1, Simona Brillante1, Lucia Raimondo1, Concetta Di Mauro1, Roberta Marciano1, Roberta Clara Orsini1, Sandro Cosconati2, Antonio Randazzo3, Sarah J. Parsons4, Nunzia Montuori5, Bianca Maria Veneziani6, Sabino De Placido1, Roberta Rosa1,*, Roberto Bianco1,*
1Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
2DiSTABiF, Second University of Naples, Caserta, Italy
3Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
4Department of Microbiology, Immunology & Cancer Biology, Cancer Center, University of Virginia Health System, Charlottesville, Virginia, USA
5Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
6Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy
*These authors have contributed equally to this work
Roberto Bianco, e-mail: [email protected]
Keywords: Src, NSCLC, EGFR inhibitors, MEK inhibitors, drug resistance
Received: March 04, 2015 Accepted: July 23, 2015 Published: August 03, 2015
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.
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