Targeting TGF-beta Signaling in Lung Cancer

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Lung carcinogenesis in humans involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, in situ carcinoma, and finally invasive and metastatic cancers. The loss of TGF-fi-induced tumor suppressor function in tumors is believed to play a pivotal role in this transition. Resistance to TGF-fi in lung cancers occurs mostly through loss of TGF-fi type II receptor (TliRII) expression, and our preliminary data suggest that expression of TliRII is lost or weak in 77% of human lung cancers. However, it is not known how TURN expression is lost during lung tumorigenesis. Our initial experiments have resulted in an important observation that activation of the MAPK/ERK pathway causes down-regulation of TfiRII through histone deacetylation and that DMA hypermethylation has no effect on TfiRII promoter activity. In addition, we have observed that TGF-li-induced tumor suppressor function is restored in TGF-li resistant lung cancer cells via exogenous TfiRII expression or with the treatment of histone deacetylase (HDAC) inhibitor (HDI). Since the majority of lung tumors are resistant to TGF-li due to loss of TliRII, we believe that the TGF-fi pathway could be a potential target of HDIs for chemothrapeutic intervention. We have formulated the following hypotheses: 1) Loss of TfiRII expression in lung cancer is mostly due to the epigenetic change, histone deacetylation, and promotes unresponsiveness to TGF-fi-induced tumor suppressor effects. 2) In the pre-malignant phase, the autocrine anti-proliferative effects of TGF-fi predominate. However, the balance shifts during tumor progression, and growth-promoting effects of TGF-fi become pronounced in the advanced stage. 3) Restoration of TGF-fi signaling by the HDI, MS-275, an anticancer drug currently in clinical trials, may be a potential alternative for therapeutic intervention of lung cancers. These hypotheses will be tested by the following specific aims: 1) To determine the molecular mechanism of down-regulation of TfiRII in lung cancer and how that can be targeted by HDAC inhibitors. 2) To determine the biological consequences of over-expression of TGF-fi and restoration of TGF-fi signaling in human lung cancer cell lines. The long term objective of this study is to determine, at the molecular level, the mechanism by which lung tumors become resistant to TGF-fi tumor suppressor function and to provide new insights into the mechanism by which HDIs target the TGF-fi pathway in lung cancer. Increased understanding of these mechanisms should help to improve drug development and treatment of lung cancer.