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 (IC50 < 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.
Highlights
Lung cancer is one of the leading causes of cancer mortality in many countries [1,2,3]
We investigated on the proliferation inhibition effects of PD0325901 and Saracatinib as single drug therapies on a collection of 28 lung cancer cell lines
The present study shows that SRC and MEK co-inhibition by Saracatinib and PD0325901 respectively can be broadly effective in tumor growth control of a wide panel of non-small cell lung cancers (NSCLC) cell lines
Summary
Lung cancer is one of the leading causes of cancer mortality in many countries [1,2,3]. The introduction of targeted therapeutics for cancer treatment in recent years has significantly changed the practice of medical oncology and many targeted www.impactjournals.com/oncotarget therapeutics are being validated in various stages of clinical development. Some of these targeted compounds, such as Gefitinib and Erlotinib, have been approved for first-line treatment to treat advanced NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutations [5, 6]. EGFR can crosstalk with other growth factor receptors, such as insulin-like growth factor-I receptor (IGF-IR), and reduces the effectiveness of Erlotinib treatment through the activation of the AKT signaling pathway [9]
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