Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma

// Kian Ngiap Chua 1, * , Li Ren Kong 1, * , Wen Jing Sim 2, * , Hsien Chun Ng 2 , Weijie Richard Ong 3 , Jean Paul Thiery 1, 2, 4 , Hung Huynh 3 , Boon Cher Goh 1, 5, 6 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 2 Institute of Molecular and Cell Biology, A*STAR, Singapore 3 National Cancer Centre, Singapore 4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Department of Hematology-Oncology, National University Hospital, Singapore 6 National University Cancer Institute, Singapore * These authors have contributed equally to this work Correspondence to: Boon Cher Goh, e-mail: phcgbc@nus.edu.sg Keywords: mesenchymal-epithelial transition inducer, MEK and SRC inhibitor combination treatment, PD0325901, saracatinib, non-small-cell lung cancer Received: April 21, 2015      Accepted: August 07, 2015      Published: August 17, 2015 ABSTRACT Oncogenesis in non-small cell lung cancer (NSCLC) is regulated by a complex signal transduction network. Single-agent targeted therapy fails frequently due to treatment insensitivity and acquired resistance. In this study, we demonstrate that co-inhibition of the MAPK and SRC pathways using a PD0325901 and Saracatinib kinase inhibitor combination can abrogate tumor growth in NSCLC. PD0325901/Saracatinib at 0.25:1 combination was screened against a panel of 28 NSCLC cell lines and 68% of cell lines were found to be sensitive (IC 50 < 2 μM) to this combination. In Snail1 positive NSCLC lines, the drug combination complementarily enhanced mesenchymal-epithelial transition (MET), increasing both E-cadherin and Plakoglobin expression, and reducing Snail1, FAK and PXN expression. In addition, the drug combination abrogated cell migration and matrigel invasion. The co-inhibition of MAPK and SRC induced strong G1/G0 cell cycle arrest in the NSCLC lines, inhibited anchorage independent growth and delayed tumor growth in H460 and H358 mouse xenografts. These data provide rationale for further investigating the combination of MAPK and SRC pathway inhibitors in advanced stage NSCLC.