[Frontiers in Bioscience 16, 1714-1732, January 1, 2011]

Kinase-driven pathways of EGFR in lung carcinomas: perspectives on targeting therapy

Yoh Dobashi1, Shinichiro Koyama2, Yoshihiko Kanai3, Kenji Tetsuka3

1Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama, Japan 1-847 Amanuma, Omiya, Saitama Saitama  330-8503 Japan 2 Department of Pulmonary Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan 1-847 Amanuma, Omiya, Saitama Saitama  330-8503 Japan, 3 Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan 1-847 Amanuma, Omiya, Saitama Saitama  330-8503 Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. EGFR abnormalities in lung cancer
3.1. Overexpression of EGFR protein
3.2. Activation of EGFR protein
3.3. Amplification of EGFR gene
3.4. EGFR gene mutation spectrum and associated amplification
3.5. Clinicopathological significance of EGFR abnormalities
3.5.1. Overexpression
3.5.2. Amplification
3.5.3. Mutations
4. Signaling cascade of EGFR
4.1. Stats
4.2. Erk1/2
4.3. Akt
4.4. Possible correlations between EGFR status and downstream activation
5. Akt-mediated pathway
5.1. Akt, as a potential key molecule and its significance in human cancer
5.2. Akt/mTOR cascade
5.3. Involvement of mTOR in cancer
5.4. Downstream of mTOR and specific correlations between intermediate effectors
5.5. Constitutive activation of the EGFR-Akt-mTOR cascade
5.6. Clinicopathological analysis
6. Molecular targeted therapy in lung cancer
6.1. Development of EGFR-targeted therapy
6.2. Resistance against TKIs
6.3. Targeting cancers with wild-type EGFR
6.4. Rationale for targeting Akt/mTOR signaling in human cancers
6.5. Multitargeted therapies
7. Perspective
8. Acknowledgements
9. References

1. ABSTRACT

Despite remarkable advances in oncology medicine, the prognosis of lung cancer patients has not greatly improved over the past few decades. To overcome the current limit, new classes of agents that specifically target particular cascades have been developed. Gefitinib and erlotinib, which are tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR), have provided hope for better survival. The relationship between the sensitivity to gefitinib and the tumors' EGFR mutations have allowed the selective and accelerated use of these therapies. However, their efficacy is still limited, predominantly due to side effects and drug resistance. Further development of rational clinical strategies will require greater clarification of the key signaling factors downstream of EGFR which are potential targets for cancer therapies. In this review, we describe the various observed abnormalities in EGFR, the mechanisms of activation of several critical signaling cascades in lung cancer. Summarizing the data gleaned from preclinical, and clinicopathological aspects, we discuss the molecular mechanisms that may underlie a possible successful response to the blockade of EGFR and/or its downstream signaling.