Role of the IGF Axis in Lung Carcinogenesis: Novel strategies for Lung Cancer Prevention and Therapy

Abstract

Lung cancer is one of the leading causes of human death worldwide. Despite advances in therapeutic regimens, the efficacy of currently available lung cancer therapies is still limited, emphasizing the necessity to develop novel strategies for lung cancer prevention and therapy. Many previous studies have demonstrated the crucial role of the insulin-like growth factor receptor (IGF1R) signaling pathway in the cancer development and progression and anticancer drug resistance in several types of cancer including lung cancer. In our recent studies, we observed elevated expression of IGFs along with IGF-1R activation in early stage of human lung carcinogenesis. Tobacco carcinogens and stress hormone induced a rapid IGF2 secretion and IGF-1R activation via voltage-dependent calcium channel (VDCC)-intervened calcium influx in airway epithelial cells, ultimately leading to lung tumor formation. Moreover, blockade of the VDCC-mediated Ca2+ influx by treatment with clinically available antihypertensive agents, such as voltage-dependent calcium channel blockers, significantly suppressed tobacco carcinogens- and chronic stress-induced lung carcinogenesis. Publicly available database revealed inverse correlation between use of calcium channel blockers and lung cancer diagnosis. These results clearly show the potential of the IGF axis as a target in lung cancer chemoprevention. However, clinical studies utilizing IGF-1R-targeted agents have shown disappointing results. We have demonstrated that targeting the IGF signaling leads to activation of bypass signaling via cancer cell reprogramming and the communication with stroma cells, eventually leading to tumor relapse and metastatic tumor growth. In this presentation, I will discuss the role of the IGF signaling in lung cancer development and progression, the mechanisms underlying resistance to IGF1R-targeted therapies, and novel alternative approaches to block the IGF signaling activation for lung cancer prevention and therapy.