Introduction Non–small-cell lung cancer (NSCLC) accounts for approximate- ly 80%-85% of all cases of lung cancer, and it has been estimated that more than 215,000 new cases will be diagnosed in the United States in 2008. As most patients have advanced unresectable disease at the time of diagnosis, their prognosis is poor. Patients with NSCLC with unresectable stage III disease account for approximately 40% of all patients with lung cancer. The standard treatment for unresectable stage III NSCLC is the concurrent admin- istration of a platinum-based chemotherapy regimen and thoracic radiation. At present, no single chemoradiation therapy regimen can be considered standard. Chemotherapy concurrently with chest radiation therapy significantly improves the survival of patients with unresectable stage IIA and IIIB disease and is now the treatment of choice. 1,2 Current research focuses on the development of new agents and the assessment of combinations of therapies and the integration of new agents. In this context, it becomes critically important to identify potential biologic targets, the blockade of which would affect multiple downstream signaling cascades. In this review, we focus on these new agents and on promising new combinations with radiation therapy for the treatment of lung cancer (Table 1.) 3,4 1 Department of Medical Oncology, Hospital Universitario Clínica Puerta de Hierro-Majadahonda 2 Hospital Ramón y Cajal 3 Department of Radiation Oncology, Hospital Universitario Clínica Puerta de Hierro-Majadahonda Madrid, Spain Submitted: Jul 6, 2009; Revised: Sep 17, 2009; Accepted: Oct 9, 2009 Address for correspondence: Mariano Provencio, MD, PhD, Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro-Majadahonda, Calle Manuel de Falla, 1, Madrid 28222, Spain Fax: 34-91-344-5190; e-mail: mprovenciop@gmail.com This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400. Clinical Lung Cancer March 2010 | 91 Abstract New Molecular Targeted Therapies Integrated With Radiation Therapy in Lung Cancer Mariano Provencio, 1 Antonio Sánchez, 1 Pilar Garrido, 2 Francisco Valcárcel 3 Non–small-cell lung cancer (NSCLC) accounts for approximately 80%-85% of all cases of lung cancer; for patients with stage III disease, it accounts for approximately 40% of all cases. The treatment for unresectable stage III NSCLC is the combination of platinum-based chemotherapy and thoracic radiation. In this article, new targeted agents under investigation for possible integration into the combined therapy are reviewed. One of the most promising strategies is the inhibition of the epidermal growth factor receptor (EGFR) pathway. Radiation activates EGFR signaling, leading to radio-resistance by inducing cell proliferation and enhanced DNA repair. Several preclinical models have shown synergistic activity when cetuximab was combined with radiation therapy. Some phase II trials have evaluated the safety and efficacy of synchronous cetuximab and radiation therapy with promising results. Gefitinib has a radiosen- sitizing effect on cell lines and has been investigated in combination with radiation therapy for unresectable stage III NSCLC. However, disappointing results were observed in the maintenance treatment with gefitinib after chemoradia- tion therapy. Erlotinib has been tested in a phase I trial with chemoradiation therapy. Radiation induces tumor death by damaging cell membranes, DNA, and microvascular endothelial cells, which in response increase proangiogenic growth factors. Antiangiogenic agents reduce vascular density but improve tumor oxygenation. Use of vascular en- dothelial growth factor receptor (VEGFR) inhibitors enhances the therapeutic efficacy of irradiation in human NSCLC by hindering the repair of sublethal radiation damage. Trials combining erlotinib and bevacizumab with thoracic ra- diation are ongoing. New strategies must be developed for the integration of this triple-combination treatment. As radiation therapy enhances HSP90 chaperone function, causing radio-resistant lung cancer cells, therapeutic agents that block this path are likely candidates for decreasing radio-resistance by suppressing HIF-1α and VEGF expression and thus inhibiting the survival and angiogenic potential of lung cancer cells. Aurora kinase inhibitors with radiation therapy seem to have an additive effect in preclinical models in NSCLC and mesothelioma. Clinical Lung Cancer, Vol. 11, No. 2, 91-97, 2010; DOI: 10.3816/CLC.2010.n.012 Keywords: Bevacizumab, Cetuximab, Chemoradiotherapy, Erlotinib, Gefitinib, HSP90, Stage III non–small-cell lung cancer Review