Fibroblast Growth Factor Receptor (FGFR): A New Target for Non-small Cell Lung Cancer Therapy.

Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.

CD133-Positive Cells from Non-Small Cell Lung Cancer Show Distinct Sensitivity to Cisplatin and Afatinib.

The standard of care for advanced non-small cell lung cancer (NSCLC) consists in cisplatin-combination chemotherapy. In patients bearing tumors with activating mutations of the epidermal growth factor receptor (EGFR), the inhibition of the EGFR intracellular tyrosine kinase can induce up to 80 % response rates. However, both therapeutic strategies will eventually lead to recurrent disease due to the development of drug resistance. The identification of rare cancer stem-like cells able to repopulate the tumor, after failure to standard treatment modalities, has led to characterize these cells as potential therapeutic targets. This article will address the role of the CD133/EpCAM stem cell-related markers and explore cell sensitivity to cisplatin and to the EGFR-tyrosine kinase inhibitor, afatinib. Three human NSCLC cell lines, one wild-type (A549) and two harboring EGFR mutations (H1650 and H1975), as well as 20 NSCLC primary cultures, were grown in non-differentiating culture conditions for stem cell enrichment. Flow-cytometry analyses of CD133 and EpCAM and cell sensitivity to cisplatin and afatinib were performed. Moreover, the expression of activated EGFR was assessed by Western blot. The cell lines and primary cultures grown in non-differentiating culture conditions were enriched with CD133/EpCAM-positive cells and were significantly more resistant to cisplatin and more sensitive to afatinib as compared to the differentiated counterpart. In addition, increased EGFR-phosphorylation in non-differentiated cultures was observed. The present findings suggest that afatinib might be beneficial for patients bearing tumors with constitutively activated EGFR, to target chemo-resistant CD133/EpCAM-positive cancer stem cells.

Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.