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Targeting mTOR Signaling for Lung Cancer Therapy

  • Shi-Yong Sun
    Affiliations
    Departments of Hematology & Oncology (SYS and FRK) and Pharmacology (HF), Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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  • Haian Fu
    Affiliations
    Departments of Hematology & Oncology (SYS and FRK) and Pharmacology (HF), Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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  • Fadlo R. Khuri
    Correspondence
    Address correspondence to: Fadlo R. Khuri, MD, or Shi-Yong Sun, PhD, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA 30322.
    Affiliations
    Departments of Hematology & Oncology (SYS and FRK) and Pharmacology (HF), Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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      The mammalian target of rapamycin (mTOR), a 289 kD serine/threonine kinase, belongs to the phosphatidylinositol kinase-related kinase family. It plays a central role in regulating cell growth, proliferation, and survival, in part by regulation of translation initiation.
      • Bjornsti MA
      • Houghton PJ
      The TOR pathway: A target for cancer therapy.
      • Sawyers CL
      Will mTOR inhibitors make it as cancer drugs?.
      • Hay N
      • Sonenberg N
      Upstream and downstream of mTOR.
      In response to mitogen or nutrient stimulation, mTOR regulates translation initiation, primarily through two distinct pathways: ribosomal p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Activated p70S6K by mTOR further phosphorylates the 40S ribosomal protein S6, leading to enhancement of the translation of mRNAs. In addition, mTOR also directly phosphorylates 4E-BP1, which triggers additional phosphorylation events that cause phosphorylated 4E-BP1 to dissociate from eIF4E, thereby increasing the cap-dependent translation of mRNAs, such as cyclin D1 and c-Myc (Fig. 1).
      • Bjornsti MA
      • Houghton PJ
      The TOR pathway: A target for cancer therapy.
      • Sawyers CL
      Will mTOR inhibitors make it as cancer drugs?.
      • Hay N
      • Sonenberg N
      Upstream and downstream of mTOR.
      Therefore, phospho-p70S6K (or phospho-S6) and phospho-4E-BP1 are common read-outs of the mTOR signaling.
      Figure thumbnail gr1
      FIGURE 1.mTOR signaling and its regulation by PI3K/Akt and LKB1/AMPK. GRs, growth factor receptors; IRS, insulin receptor substrate; PIP3, phosphatidylinositol 3,4,5-triphosphate.
      The PI-3 kinase (PI3K)/Akt signaling represents a major cell survival pathway. Its activation has long been associated with malignant transformation and apoptotic resistance.
      • Vivanco I
      • Sawyers CL
      The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
      It is generally thought that mTOR functions downstream of the PI3K/Akt pathway and is phosphorylated (or activated) in response to stimuli that activate the PI3K/Akt pathway (Fig. 1).
      • Bjornsti MA
      • Houghton PJ
      The TOR pathway: A target for cancer therapy.
      • Hay N
      • Sonenberg N
      Upstream and downstream of mTOR.
      In addition to positive regulation of the mTOR axis by PI3K/Akt, recent evidence has linked LKB1, a serine/threonine kinase with tumor suppression activity, to the negative regulation of the mTOR axis.
      • Shaw RJ
      • Bardeesy N
      • Manning BD
      • et al.
      The LKB1 tumor suppressor negatively regulates mTOR signaling.
      It has been proposed that, in response to cellular energy stress, AMP-activated protein kinase (AMPK) is activated through LKB1-mediated phosphorylation and then phosphorylates TSC2 (or tuberin) to enhance TSC2 function. TSC2 subsequently inhibits mTOR function via TSC2’s GAP activity toward the Rheb small GTPase (Fig. 1).
      • Inoki K
      • Li Y
      • Zhu T
      • Wu J
      • Guan KL
      TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
      Under normal conditions, LKB1/AMPK activation overrides the mitogenic signal from Akt and tightly controls mTOR signaling. However, in the absence of LKB1, AMPK cannot be activated, nor can mTOR be inactivated, in response to cellular energy stress.
      • Vivanco I
      • Sawyers CL
      The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
      • Corradetti MN
      • Inoki K
      • Bardeesy N
      • DePinho RA
      • Guan KL
      Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome.
      PI3K/Akt is one of the best characterized pathways downstream of the Ras oncogene.
      • Downward J
      Targeting RAS signaling pathways in cancer therapy.
      Because of mutation and overexpression of growth factors and/or their receptors, the Ras signaling pathway is frequently activated in human non-small cell lung cancer (NSCLC).
      • Mitsuuchi Y
      • Testa JR
      Cytogenetics and molecular genetics of lung cancer.
      • Sekido Y
      • Fong KM
      • Minna JD
      Molecular genetics of lung cancer.
      • Hirsch FR
      • Scagliotti GV
      • Langer CJ
      • Varella-Garcia M
      • Franklin WA
      Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies.
      As a result, the PI3/Akt pathway is also frequently activated in human NSCLC, as demonstrated in several studies.
      • Brognard J
      • Clark AS
      • Ni Y
      • Dennis PA
      Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.
      • Lee SH
      • Kim HS
      • Park WS
      • et al.
      Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study.
      • Balsara BR
      • Pei J
      • Mitsuuchi Y
      • et al.
      Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions.
      • Tsao AS
      • McDonnell T
      • Lam S
      • et al.
      Increased phospho-AKT [Ser(473)] expression in bronchial dysplasia: Implications for lung cancer prevention studies.
      • David O
      • Jett J
      • LeBeau H
      • et al.
      Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage.
      Although somatic LKB1 mutations are rare in most sporadic tumor types,
      • Avizienyte E
      • Loukola A
      • Roth S
      • et al.
      LKB1 somatic mutations in sporadic tumors.
      • Avizienyte E
      • Roth S
      • Loukola A
      • et al.
      Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.
      there is a high frequency of LKB1 mutations in human NSCLC, particularly adenocarcinomas. It has been reported that LKB1 gene alterations were present in 54% of lung adenocarcinoma cell lines and in approximately 30% of primary lung adenocarcinomas.
      • Sanchez-Cespedes M
      • Parrella P
      • Esteller M
      • et al.
      Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.
      • Carretero J
      • Medina PP
      • Pio R
      • Montuenga LM
      • Sanchez-Cespedes M
      Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene.
      Thus, it seems that LKB1 inactivation is a critical event in the development of sporadic lung adenocarcinomas.
      Because of the constitutive activation of PI3K/Akt signaling and frequent mutations or inactivation of the LKB1 gene, it is likely that the mTOR axis is dysregulated and activated in human NSCLC, particularly adenocarcinomas. Indeed, a recent report by Balsara et al.
      • Balsara BR
      • Pei J
      • Mitsuuchi Y
      • et al.
      Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions.
      indicates that phosphorylation or activation of mTOR was detected in 74% of NSCLC, which was significantly associated with activation of Akt. Therefore, the mTOR signaling axis represents a highly promising therapeutic target for lung cancer therapy. Rapamycin and its derivatives CCI-779 and RAD001 are novel anticancer drugs developed to modulate mTOR activation.
      • Bjornsti MA
      • Houghton PJ
      The TOR pathway: A target for cancer therapy.
      • Hay N
      • Sonenberg N
      Upstream and downstream of mTOR.
      Our studies have shown that rapamycin is effective in inhibiting the growth of human NSCLC cells.
      • Sun SY
      • Rosenberg LM
      • Wang X
      • et al.
      Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.
      In animal models, rapamycin effectively inhibited the growth of a NSCLC tumor
      • Boffa DJ
      • Luan F
      • Thomas D
      • et al.
      Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer.
      and alveolar epithelial neoplasia induced by oncogenic K-Ras.
      • Wislez M
      • Spencer ML
      • Izzo JG
      • et al.
      Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras.
      Several recent studies have shown that an mTOR inhibitor such as RAD001 sensitizes cancer cells to chemotherapy,
      • Beuvink I
      • Boulay A
      • Fumagalli S
      • et al.
      The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.
      • Mondesire WH
      • Jian W
      • Zhang H
      • et al.
      Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells.
      radiation,
      • Shinohara ET
      • Cao C
      • Niermann K
      • et al.
      Enhanced radiation damage of tumor vasculature by mTOR inhibitors.
      or overcomes chemoresistance
      • Wu C
      • Wangpaichitr M
      • Feun L
      • Kuo MT
      • Robles C
      • Lampidis T
      • Savaraj N
      Overcoming cisplatin resistance by mTOR inhibitor in lung cancer.
      in several types of cancer cells, including lung cancer cells. Our unpublished data also show that the combination of rapamycin and docetaxel is synergistic in inhibiting the growth of lung cancer cells. Therefore, we postulate that mTOR inhibitors, like other signal transduction inhibitors, could be more efficacious if used in combination with other agents or therapies, such as chemotherapy or other targeted agents in lung cancer treatment, as long as these combinations are based on sound preclinical and clinical drug development principles. Our recent data clearly show that mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K/Akt survival pathway, in human lung and other types of cancer cells.
      • Sun SY
      • Rosenberg LM
      • Wang X
      • et al.
      Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.
      Thus, one rational approach for mTOR-targeted lung cancer therapy is to use an mTOR inhibitor in combination with a drug that blocks PI3K/Akt activation such as a PI3K inhibitor, as we demonstrated in our study.
      • Sun SY
      • Rosenberg LM
      • Wang X
      • et al.
      Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.

      ACKNOWLEDGMENTS

      This study supported by the Winship Cancer Institute faculty start-up research fund (to SYS), the Georgia Cancer Coalition Distinguished Cancer Scholar award (to SYS), Department of Defense IMPACT grant W81XWH-05-0027 (to FRK and SYS), and the Georgia Cancer Coalition Research Award (to HF). SYS and FRK are Georgia Cancer Coalition Distinguished Cancer Scholars.

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