The mammalian target of rapamycin (mTOR) is a serine-threonine kinase and plays a critical role in promoting cell growth and survival, primarily through interactions with other proteins such as raptor (forming mTOR complex 1, mTORC1) and rictor (forming mTOR complex 2, mTORC2). This pathway is frequently activated in human cancers including lung cancer and thus represents an attractive cancer therapeutic target. The conventional mTOR inhibitors rapamycin and its analogues (rapalogs) are specific allosteric inhibitors of mTORC1. Although some of them are FDA-approved drugs for treatment of renal cancer, the single-agent activity of rapalogs in most other tumor types has been modest at best. Thus, great effort has been made to develop ATP-competitive inhibitors of mTOR (i.e., mTOR kinase inhibitors;TORKinibs), which inhibit function of both mTORC1 and mTORC2. The novel TORKinibs may provide additional clinical benefits since they inhibit mTORC2, which functions as an Akt S473 kinase. Indeed, TORKinibs possess promising preclinical anticancer activity. However, the activity of TORKinibs in lung cancer has not been reported or well studied. Moreover, the impact of genetic alterations on cell sensitivity to TORKinibs is unknown. In this proposal, we will test the hypothesis that TORKinibs alone or in combination with other cancer therapeutic agents will be effective in treatment of non-small cell lung cancer (NSCLC), particularly those with CDKN2A mutation or CDK4 amplification, by accomplishing three specific aims: 1) To evaluate the efficacy of TORKinibs against the growth of NSCLC cells in vitro and in vivo and their effects on repressing mTOR signaling;2) To demonstrate the impact of genetic alteration of CDKN2A gene and its pathway on cell responses to TORKinibs;and 3) To determine whether TORKinibs cooperates with TRAIL to augment apoptosis and to exert enhance anticancer activity in NSCLC and understand the underlying mechanisms. This proposal will allow us to evaluate the therapeutic potential of the novel TORKinibs alone or in combination with others against NSCLC, and to determine the impact of genetic alteration of CDKN2A or CDK4 on cell responses to this group of agents.

Public Health Relevance

This proposal will evaluate the therapeutic potential of novel mTOR kinase inhibitors either alone or in combination with other agents against lung cancer and determine the impact of genetic alterations on cell responses to these inhibitors. Our findings will guide clinically better application of this group of agents for treatment of lung cancer. Thus, the study is highly translational with potential clinical impact.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA160522-01A1S1
Application #
8547856
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Ogunbiyi, Peter
Project Start
2012-09-01
Project End
2017-03-31
Budget Start
2012-09-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$164,541
Indirect Cost
$59,066
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Shi, Puyu; Oh, You-Take; Deng, Liang et al. (2017) Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation. Clin Cancer Res 23:6567-6579
Li, S; Oh, Y-T; Yue, P et al. (2016) Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells. Oncogene 35:642-50
Shi, Puyu; Oh, You-Take; Zhang, Guojing et al. (2016) Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett 380:494-504
Yao, Weilong; Oh, You-Take; Deng, Jiusheng et al. (2016) Expression of Death Receptor 4 Is Positively Regulated by MEK/ERK/AP-1 Signaling and Suppressed upon MEK Inhibition. J Biol Chem 291:21694-21702
Koo, Junghui; Wu, Xiaoyun; Mao, Zixu et al. (2015) Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J Biol Chem 290:14120-9
Koo, Junghui; Yue, Ping; Deng, Xingming et al. (2015) mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation. Mol Cell Biol 35:2344-55
Yao, Weilong; Yue, Ping; Zhang, Guojing et al. (2015) Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. Cancer Lett 364:70-8
Koo, Junghui; Wang, Xuerong; Owonikoko, Taofeek K et al. (2015) GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth. Oncotarget 6:8974-87
Koo, Junghui; Yue, Ping; Gal, Anthony A et al. (2014) Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth. Cancer Res 74:2555-68
Sun, Shi-Yong (2013) Impact of genetic alterations on mTOR-targeted cancer therapy. Chin J Cancer 32:270-4

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