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Editorials |
Department of Biochemistry and Molecular Biology and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
Address correspondence to: Dr. James P. Calvet, Department of Biochemistry and Molecular Biology and the Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160. Phone: 913-588-7424; Fax: 913-588-7440; E-mail: jcalvet{at}kumc.edu
Polycystic kidney disease (PKD) has a number of characteristics that make it uniquely challenging for the development of therapies to slow disease progression. Renal cystic diseases result from the neoplastic growth of numerous fluid-filled cysts, often accompanied by increased apoptosis, tissue remodeling, inflammation, and fibrosis (1–3). The slow, inexorable growth of these renal cysts, particularly in the adult forms of the disease, makes PKD an unlikely candidate for cancer chemotherapeutic drugs designed to attack rapid cell proliferation.
However, unlike cancer chemotherapy, which is designed to eliminate tumors, PKD chemotherapy only has to slow cyst growth to be successful. It is not necessary to eliminate the cysts as long as renal function can be preserved and significantly extended. But any drug used to treat PKD would have to be tolerated over a lifetime, as it is likely that cysts would continue to grow, or new cysts would form de novo from normal renal tubule cells, once therapy was stopped.
A number of therapeutic interventions designed specifically to inhibit cell proliferation have been tested in a variety of animal models of PKD. These interventions include paclitaxel, lovastatin, EGF receptor (EGFR) tyrosine kinase inhibition, TNF-
converting enzyme inhibition, c-Src inhibition, c-Myc antisense oligos, and rapamycin—these therapies have exhibited limited success or mixed outcomes (4–7). The vasopression receptor antagonists, which have the effect of lowering intracellular cAMP, have shown remarkable success (6,8). In this issue of JASN, Omori et al. (9) present a study in which they tested another cell proliferation inhibitor from the cancer chemotherapeutic arsenal. In this paper, the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) kinase (MEK) inhibitor PD184352 (now named CI-1040) is shown to effectively block cyst growth and kidney enlargement, and to preserve renal function, when given to pcy/pcy mice that have nephronophthisis (NPHP3), an adolescent form of recessive PKD (10).
PD184352 inhibits the Ras/MAPK pathway by targeting the MAPK kinase, MEK, which activates ERK by phosphorylating it on tyrosine and threonine residues (Figure 1). The Ras/MAPK pathway mediates most growth factor (GF) receptor–mediated signaling. Activation of a Ras family member (H-Ras, K-Ras, N-Ras) leads directly to activation of the Raf kinases (Raf-1, A-Raf, B-Raf). The Rafs are also called MAPK kinase kinases because they phosphorylate and activate MEK1 and MEK2. The MEKs, in turn, phosphorylate ERK1 and ERK2, their only known targets. Then ERK, among other things, phosphorylates and activates transcription factors affecting gene expression and ultimately cell proliferation.
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The rationale for targeting the MEK/ERK pathway is based on previous studies that showed that cAMP-dependent proliferation of cultured human autosomal dominant PKD (ADPKD) cyst–lining epithelial cells is mediated through the activation of ERK (12–14) and that P-ERK levels are elevated in the cystic epithelium of Han:SPRD +/cy rat kidneys (15). It is now thought that the cell proliferation phenotype in PKD involves an abnormal response of cyst epithelial cells to cAMP that may be a consequence of dysregulated calcium signaling (14,16). In cyst epithelial cells, cAMP agonists stimulate the B-Raf/MEK/ERK pathway (Figure 1, right). By contrast, cAMP inhibits ERK activity and slows proliferation of normal renal epithelial cells (Figure 1, left). These studies have also shown that normal renal epithelial cells can be switched from a cAMP-inhibited phenotype to a cAMP-stimulated phenotype by lowering intracellular calcium (14), and that ADPKD cells can be rescued (switched back) by raising intracellular calcium (16).
The basis for this phenotypic switch appears to be the response of B-Raf to cAMP. In normal cells (Figure 1, left), B-Raf is repressed by Akt (also called protein kinase B) in a phosphoinositide-3 kinase (PI3K)- and calcium-dependent manner. By contrast, in ADPKD cells and in calcium-restricted cells (Figure 1, right), Akt activity is decreased, thus allowing B-Raf to be activated by cAMP. Activation of B-Raf leads to MEK and ERK activation and results in increased cell proliferation. Another MEK inhibitor, PD98059, was shown to block ERK activation and prevent this cAMP-dependent cell proliferation in PKD cells (13,14). Thus, it appears that the key to the aberrant cell proliferation in PKD is cAMP-dependent B-Raf activation, with downstream activation of MEK and ERK. The paper by Omori et al. further confirms the importance of MEK/ERK signaling, now in a model of NPHP3, suggesting that renal cystic diseases in general may share a common, characteristic signaling pathway. Importantly, this paper shows that MEK inhibition slows cyst growth in vivo.
A valid question to ask is whether this anticancer drug would hold up to the requirements of a PKD therapeutic trial. In other words, will this compound be safe and effective over decades? PD184352 has been through phase I and phase II clinical trials to evaluate its effectiveness toward a variety of solid tumors, the large majority carrying RAS gene mutations (17–19). It was found to be highly specific (MEK is the only known target) and well tolerated at the doses tested. However, although it looked promising initially during phase I trials, it showed disappointing antitumor effectiveness during phase II trials. Nevertheless, a >50% reduction in ERK phosphorylation could be demonstrated in tumor tissue, indicating that the drug did reach its intended target.
So is there cause for hope? It now turns out that the pathway by which MEK is activated in tumors may dramatically affect its sensitivity to PD184352. For unknown reasons, tumors that contain B-RAF mutations are "exquisitely sensitive" to MEK inhibition, in contrast to tumors that contain RAS mutations or other mutations that lead to high P-ERK levels (20). Logic would suggest that tumors sharing common pathways leading to MEK/ERK activation would be equally sensitive to PD184352—but apparently this is not the case. This could explain the poor responses of PD184352 in phase II trials, as most of the tumors had RAS rather than B-RAF mutations (20). Is it possible, then, that the success of PD184352 in treating cyst growth and kidney enlargement (9) is because these cells contain B-Raf that is constitutively active due to reduced Akt activity—this B-Raf being activated not by mutation but by cAMP? If so, PD184352 and new-generation MEK-specific inhibitors may hold promise for treating PKD.
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Acknowledgments |
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Footnotes |
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See related article, "Extracellular Signal-Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease," on pages 1604-1614.
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  J. P. Calvet Strategies to Inhibit Cyst Formation in ADPKD Clin. J. Am. Soc. Nephrol., July 1, 2008; 3(4): 1205 - 1211. [Abstract] [Full Text] [PDF]
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