(Chest. 2004;125:141S-144S.)
© 2004
American College of Chest Physicians
Role of Protein Kinase B-Dependent Signaling in Lung Tumorigenesis*
Jonathan M. Kurie, MD
* From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX.
Correspondence to: Jonathan M. Kurie, MD, Box 432, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jkurie{at}mdanderson.org
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Abstract
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Recent studies have defined the survival pathways activated by receptor tyrosine kinases that are critical in the transformation of human bronchial epithelial cells and in maintaining the survival of non-small cell lung cancer (NSCLC) cells. Protein kinase B (AKT) is one element of receptor tyrosine kinase signaling that is activated in bronchial premalignancy and NSCLC. Recent studies have shown that AKT cooperates with the stress kinase mitogen-activated protein kinase kinase 4 to maintain the survival of NSCLCs. These studies illustrate the importance of understanding the interactions between survival pathways and developing inhibitors to specific kinases that can be used alone or in combination in clinical trials for lung cancer prevention and treatment.
Key Words: non-small cell lung cancer • protein kinase B • mitogen-activated kinase kinase-4
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Introduction
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Lung cancer remains the primary cause of cancer-related death in both men and women in the United States.1 Because the available therapeutic modalities are ineffective in treating lung cancer, investigators have focused their efforts on prevention. Exposure to cigarette smoke confers the greatest risk, with approximately 90% of all lung cancers occurring in smokers; thus, smoking cessation campaigns have been a major focus of prevention efforts. Although smoking cessation has been shown to reduce lung cancer risk, former smokers continue to have an increased risk relative to never-smokers.2 Currently, 50% of all non-small cell lung cancers (NSCLCs) are diagnosed in former smokers,2 demonstrating the need for additional strategies in former smokers. Toward this goal, preventive therapies have been an important focus of lung cancer research. The agents most frequently studied in preclinical and clinical lung cancer prevention studies are retinoids. These are natural and synthetic compounds related to vitamin A (retinol) and retinoic acid. The multiple, large-scale, lung cancer prevention trials performed to date in the United States and Europe (ie, 
-Tocopherol-ß Carotene [ATBC], ß-Carotene and Retinol Efficacy Trial [CARET], and the United States Intergroup Study) have failed to demonstrate activity of retinoids in the prevention of lung cancer.3 Clearly, we need a new approach to lung cancer prevention. This will require discovering agents that target molecules required for the survival of bronchial premalignancy and NSCLC and the ability to identify individuals likely to respond to these interventions.
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PI3K: A Key Regulator of Intracellular Phospholipids
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Class I PI3K consists of a family of heterodimeric complexes, each composed of a p110 catalytic subunit and a regulatory subunit that exists predominately in a p85 form.456 The known gene family members for p85 (,ß,
) and p110 (,ß,
,) are expressed in a tissue-specific fashion. p85 and ß can also exist in smaller forms (p50 and p55). PI3K phosphorylates the D3 position of phosphatidylinositol on PI(4)P and PI(4,5)P to produce PI(3,4)P2 and PI(3,4,5)P3. The 3' sites of PI(3,4)P2 and PI(3,4,5)P3 are dephosphorylated by the PTEN tumor suppressor, whereas the 5' site of PI(3,4,5)P3 is dephosphorylated by SHIP to produce PI(3,4)P2. These mechanisms tightly regulate the levels of 3-phosphorylated phosphatidylinositol in the cell. PI(3,4,5)P3 and PI(3,4)P2 recruit specific intracellular proteins to the cytoplasmic membrane through binding to pleckstrin homology FYVE and C2 domains, an essential event in the activation of PI3K-dependent kinases such as 3-phosphoinositide-dependent protein kinase (PDK-1) and protein kinase B (AKT).
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PI3K-Dependent Survival Pathways
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Studies have shown that activation of the PI3K pathway is required for cellular survival and transformation. AKT phosphorylates a number of proapoptotic and antiapoptotic proteins, including the Bcl-2 family member BAD, caspase-9, cyclic adenosine monophosphate response element-binding protein, I-kappa B kinase (IKK)-, and forkhead transcription factor-1.7 PI3K-dependent signaling in cancer cells is activated by genetic and/or epigenetic alterations of the p85 regulatory subunit of PI3K, the p110/ß catalytic subunits of PI3K, AKT2, AKT3, and PTEN.8910111213141516 In vitro studies17181920212223 have confirmed that PI3K and its downstream mediators have oncogenic effects, and that PTEN has tumor-suppressor properties. In addition to its role as an activator of AKT, PI3K activates RAC-1, which plays a key role in the reorganization of the actin cytoskeleton induced by growth factors or oncogenic ras.2425 Ras activates RAC-1 indirectly as a consequence of PI3K-mediated phosphorylation of membrane phosphatidylinositols.25 PI(3,4,5)P3 binds to a guanosine nucleotide exchange factor son of sevenless (SOS), which is then stimulated to load RAC-1 with guanosine triphosphate (GTP), an essential event in RAC-1 activation. RAC-1, in turn, activates downstream signaling through p21-activated kinase (PAK)-1 and its mediators, which include mitogen-activated protein kinase kinase-4 (MKK4) and its substrates cJun N-terminal kinase (JNK) and p38/HOG1.26
Previous studies27 have shown that certain cancer cell types with PTEN gene loss have constitutively active PI3K and undergo apoptosis in response to pharmacologic or genetic inhibition of PI3K. Most NSCLC cell lines demonstrate hallmarks of PI3K pathway activation, such as phosphorylation of AKT and its downstream mediators, but have a wild-type PTEN gene.282930313233 Despite having wild-type PTEN, NSCLC cells undergo apoptosis in response to PI3K pathway inhibition.28 The apoptosis reported by Brognard et al28 may depend in part on the absence of serum, which rescues cells from apoptosis induced by PI3K inhibition.22233435 Thus, serum-induced activation of other peptide growth factor-induced signaling pathways can overcome the proapoptotic effect of PI3K inhibition, indicating that downstream mediators of AKT and other receptor tyrosine kinase-dependent pathways interact to maintain cancer cell survival.
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The PI3K Pathway Is Activated in Bronchial Premalignancy and NSCLC
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Previous studies282930313233 have reported increased expression of p-AKT (Ser473) in NSCLC, providing evidence of AKT activation in fully transformed bronchial epithelium. AKT activation occurs in NSCLC through amplification of the p110 catalytic subunit, epigenetic silencing of the PTEN gene expression, and other undefined mechanisms.282933 Immunohistochemical studies indicate that AKT is activated in bronchial dysplasia, suggesting that this biochemical event is important in the genesis of a subset of NSCLCs.36 Further, pharmacologic and genetic approaches have shown that AKT interacts with MKK4-dependent pathways to maintain NSCLC cell survival.37 Inhibition of PI3K-dependent signaling alone induces proliferative arrest, whereas inhibition of both PI3K and MKK4/JNK-dependent pathways induces apoptosis. Thus, in the setting of wild-type PTEN, PI3K-dependent, and MKK4/JNK-dependent pathways appear to cooperate to maintain NSCLC cell survival.
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Future Clinical Trials to Target AKT-Dependent and MKK4-Dependent Pathways in NSCLC
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In summary, these findings support clinical trials to test agents that target the PI3K-dependent and MKK4-dependent pathways in individuals at risk for or with a diagnosis of NSCLC. Several agents that target these pathways are currently in preclinical or clinical development. CCI-779 is an inhibitor of mammalian target of rapamycin (TOR), a substrate of AKT, which has demonstrated activity in preclinical models of prostate cancer and is currently undergoing phase I/II clinical trials.38 KP-392 and KP-307 inhibit integrin-linked kinase, which activates AKT, and has demonstrated anticancer activity in animal models.39 SP600125 inhibits JNK, a downstream mediator of MKK4, and suppresses the growth of NSCLC cells in soft agar.40 Future clinical trials designed to target these molecules, alone and in combination, would be appropriate in lung cancer prevention and therapy.
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Footnotes
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Abbreviations: AKT = protein kinase B; MKK4 = mitogen-activated protein kinase kinase-4; NSCLC = non-small cell lung cancer
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References
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Abstract
Introduction
