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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2954-2963 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.141
The Biology and Clinical Relevance of the PTEN Tumor Suppressor PathwayFrom the Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Address reprint requests to William R. Sellers, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: william_sellers{at}dfci.harvard.edu
Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.
Cancer-causing genetic alterations fall broadly into two functional classes: those that activate cellular genes, known as oncogenes, and those that inactivate cellular genes, known as tumor-suppressor genes. Growing evidence suggests that inactivation of the tumor suppressor gene PTEN may rival mutations of p53 in frequency and in the relevance to a substantial fraction of adult epithelial tumors. Emerging therapeutics that may prove to be of particular utility in treating tumors lacking PTEN function are under clinical development—thus the impetus for providing a framework within which such inhibitors can be understood. In 1997, PTEN (phosphatase and tensin homolog deleted on chromosome 10), also known as MMAC1 and TEP1, was cloned and mapped to cytoband 10q23, a region undergoing frequent somatic deletion in tumors.1-3 In two instances, groups specifically searching either in glioma or breast cancer for a 10q23 tumor suppressor happened on the same gene, hence the alternative names.1,3 PTEN is the accepted gene symbol and will be used henceforth.
Germline mutations of tumor suppressor genes are often associated with hereditary cancer predisposition syndromes. Included among the many are the hereditary breast and ovarian cancer syndromes associated with germline mutation of BRCA1 and BRCA2 and hereditary nonpolyposis coli associated with mutations in MLH1 and MLH2. Such syndromes, though inherited in an autosomal dominant pattern, result from a recessive mutation (loss-of-function) of the tumor suppressor gene in question. Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are related hamartoma syndromes. Affected members within CS kindred develop hamartomas of the hair follicle (trichilemmomas), the mucocutaneous membranes, breast, thyroid, and intestinal tissues—detailed criteria are reviewed by Eng et al4—whereas features of BRRS include macrocephaly, lipomatosis, hemangiomatosis, and speckled penis.5 These kindred are at high risk for developing cancers of the breast and thyroid and more recently endometrial and genitourinary tract tumors were included as minor criteria in CS. In 1996, a cooperative group reported linkage analyses mapping the genetic locus for Cowden syndrome to the 10q23 region.6 The cloning of PTEN was quickly followed by the discovery of germline PTEN mutations in 80% of families with CS and 60% of subjects affected by BRRS.7-10 Thus, as with other tumor suppressor genes, inheritance of a germline PTEN mutation results in the initiation of a cancer susceptibility syndrome.
Germline mutations constitute a minor fraction of the alterations in tumor suppressor genes that contribute to the pathogenesis of human tumors, and instead are often useful heralds for the discovery of somatic mutations in sporadic nonfamilial tumors. Somatic alteration and biallelic mutation of PTEN is indeed a common event in high-grade glioblastoma, melanoma and in cancers of the prostate and endometrium. Biallelic inactivation of PTEN occurs in 30% to 40% of glioblastoma multiforme and to a lesser extent in anaplastic astrocytoma, yet is rarely seen in lower-grade glioma and glioneuronal tumors.11-16 Recently, Smith et al reported PTEN mutations in 11 of 62 anaplastic astrocytomas (18%) and in 37 of 110 GBMs (34%). Moreover, tumors harboring any PTEN alteration were associated with a significantly shorter median survival (10.4 months v 14.7 months; P < .001). Thus in glial tumors the frequency of PTEN mutation increases with tumor grade and is associated with a poor outcome.16 Knock-out mice rendered heterozygous for pten develop a number of neoplasia including those of the endometrium,17,18 and up to 50% of unselected human endometrial cancers (EC) harbor PTEN mutations. This rate approaches 80% to 90% in the endometrioid sub-type making PTEN the most commonly mutated gene in EC.19-23 In contrast to glioma, mutation of PTEN is also seen in EC precursor lesions including endometrial hyperplasia and atypical hyperplasia suggesting that PTEN loss is an early event in this disease.22,23 Intriguingly and again in contrast to glioma, in EC loss of PTEN is associated with improved survival.24 As mentioned above, the 10q23 region is a frequent target for heterozygous deletion in primary and more frequently in metastatic prostate tumors where loss-of-heterozygosity (LOH) is found in 20% to 60% of such tumors. 25 In keeping with these data, point mutations or deletions of the PTEN gene have been reported in cell lines, prostate cancer xenografts and in primary and metastatic deposits.26-32 The rate of second mutational events varies widely and is generally less frequent than the incidence of LOH; however, second PTEN mutations are found in the tumor deposits of as many as 50% of patients with metastatic disease.33 In addition, loss of the PTEN protein occurs in 20% of primary prostate tumors and this loss is highly correlated with advanced tumor grade and stage (Gleason score > 7).34 These data suggest that there is progressive loss of PTEN or accumulation of mutations in the PTEN gene in association with advancing disease. Loss or mutation of PTEN is high in malignant melanoma cell lines,35 and as is the case with prostate cancer there is discordance between the rate of LOH at 10q23 found in primary melanoma specimens and the presence of secondary mutations. Although PTEN mutations do occur in metastatic melanoma samples the frequency has ranged from 7% to 19%.36-40 Thus, when PTEN is lost there is again a correlation with more advanced disease. PTEN mutations have also been found, though to a lesser extent, in cancers of the bladder, lung, ovary, colon, and lymphatic system.31,41-44
In a number of cancers the rate of hemizygous inactivation events (LOH) in the 10q23 region significantly exceeds the rate of mutation of the remaining PTEN allele. For example, though germline PTEN mutations in CS predispose to thyroid cancer and breast cancers, only infrequent PTEN mutations (6% to 7%) have been detected in the corresponding sporadic thyroid or breast carcinomas.45-49 Similarly, mutations of PTEN in ovarian cancer are relatively rare though endometrioid sub-types of ovarian cancer may undergo PTEN loss at a greater frequency.50-52 In CS-related tumor types hemizygous inactivation of PTEN occurs with impressive frequency, yet loss of the second allele is rare. The tumor suppressor paradigm characteristically calls for loss of both functional copies of the gene and indeed many, but not all tumor suppressor genes must undergo biallelic inactivation to sustain a true loss-of-function effect. Thus, discordance between the rate of LOH and the rate of mutation of the second allele has led some to suggest that a second tumor suppressor gene is harbored in the 10q23 region. However, this difference could also result from the technical inability to detect second mutational events (low sensitivity); a gene dosage effect where loss of one allele of PTEN may have a partial tumor promoting effect; cooperation between loss of one allele of PTEN and a genetic event in a second gene or finally from epigenetic alterations in the PTEN gene, mRNA, or protein leading to a true loss-of-function. Epigenetic inactivation of the PTEN promoter was first described in prostate cancer xenografts32 where loss of PTEN protein was accompanied by promoter methylation. Although promoter methylation in primary tumor specimens has not been demonstrated, loss of the protein and loss of the PTEN mRNA does occur. For example, immunohistochemistry studies in tumors where LOH is common, but second mutations are rare, including thyroid, breast, pancreatic and ovarian cancers have demonstrated loss of PTEN protein in 30% to 50% of samples.47,53-56 In breast cancer this loss strongly correlates with lymph node metastasis and with estrogen receptor–negative tumors.54 Moreover, in thyroid and ovarian cancer such loss is accompanied by concordant activation of the PTEN regulated signaling pathway and re-expression of PTEN in thyroid tumor cell lines markedly inhibits cell growth.47 Together these data suggest that loss of PTEN as detected by Immunohistochemistry is functionally relevant.47,55 Although promoter methylation is the most common epigenetic mechanism for loss of gene expression, alternative mechanisms could contribute to the downregulation of the PTEN mRNA and/or protein. For instance, tumors might have acquired mutations in noncoding regions of PTEN, as yet unanalyzed, that are required for the expression of the transcript. In CS, for example, nonsense mutations leading to the degradation of the mRNA have been reported.7,8,10 PTEN mRNA can also be regulated through TGF-ß and through p53.2,57 The TGFß pathway is deregulated in a number of cancers, and in pancreatic cancer overexpression of TGFß1 appears to be highly correlated with reduced PTEN levels.56 The PTEN protein is also regulated by phosphorylation.58 In particular, the serine/threonine kinase CK2, upregulated in many cancers, phosphorylates the PTEN C-terminal tail and reduces PTEN activity59-61 raising the possibility that phosphorylation of PTEN by CK2 might be a mechanism contributing to the downregulation of PTEN in certain tumors retaining a wild-type PTEN allele.
PTEN: A Lipid Phosphatase The protein encoded by the PTEN gene is a phosphatase—an enzyme that facilitates the removal of phosphate groups from macromolecules (dephosphorylation). Though PTEN can dephosphorylate proteins,62 its primary biochemical and physiological targets are highly specialized plasma membrane lipids63 (Fig 1). These lipids, phosphatidylinositol-3,4,5-trisphosphate (PIP3) and phosphatidylinositol-3,4-bisphosphate are produced during cellular signaling events by the action of the lipid kinase phosphoinositide 3-kinase (PI3K) (for review see reference64). Thus, an elegant on-off switch has been evolved where the switch moves to "on" position when PI3K deposits a phosphate group on the D3 position of the inositol ring and is turned "off" when PTEN removes the phosphate group from the same position.
A critical role for this switch in both the normal response to growth signals and in the abnormal response to transforming signals was evident in the mid 1980s when PIP3 was first discovered as an evanescent molecule, the abundance of which was significantly upregulated on growth factor stimulation. At the same time, elevated PI3K activity was linked both to transformation by oncogenes, such as polyoma middle T antigen, and to mitogenic stimulation through the platelet derived growth factor receptor.65-67 The discovery of PTEN's lipid phosphatase activity, and its ability to act as an "off" switch for PI3K signaling, suggested that PTEN functioned as a tumor suppressor by directly antagonizing the activity of the PI3K signaling pathway.63 Indeed, the past several years have witnessed the production of an impressive body of experimental data supporting this model.
The Phosphoinositide 3-kinase/Akt Pathway
Once generated, the phospholipid PIP3 serves as a nidus for recruiting certain kinases to the plasma membrane including the Protein kinase B/Akt family of kinases and phosphoinositide-dependent kinase 1 (PDK1).68,69 On membrane localization Akt is activated, in part through phosphorylation by PDK1, and is then capable of phosphorylating a number of downstream targets (Fig 2). These Akt targets or substrates play key roles in regulating critical cellular functions including proliferation, apoptosis, glucose homeostasis, cell size, nutrient response and DNA damage. As predicted by this model, genetic inactivation of PTEN in human cancer cell lines, in mouse knock-out models and in lower organisms including C elegans and D melanogaster, leads to constitutive activation of this pathway70. Moreover, in each of these systems, specific cellular or organismal phenotypes resulting from PTEN loss can be accounted for and, in many cases, reversed by alterations in PI3K or Akt activity or by alterations in further downstream members of the pathway. Simply put, loss of PTEN results in alterations in cell homeostasis that depends on the activity of the PI3K pathway.
The Role of the PI3K/Akt Pathway in Oncogenesis
Similarly, in human tumors loss of PTEN function appears to be only one of a number of different genetic alterations used by tumors to constitutively activate the PI3K pathway, presumably indicating a selective growth or survival advantage accrued to tumor cells harboring such lesions. The gene PIK3CA, encoding the catalytic subunit of PI3K (p110), is located in a common amplicon at 3q26. Amplifications of this region have been reported in cancers of the ovary, cervix, head and neck and at least in certain cases, when examined in detail, such amplifications have been associated with increased PI3K activity.74-78 p85 Finally, as discussed in greater detail below, recent data suggests that the tumor suppressor genes tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2) are also key regulators of a pathway known as the mTOR pathway (mammalian Target of Rapamycin) which is, at least in part, a downstream component of the PI3K pathway (Fig 3). Thus, hereditary and possibly somatic loss-of-function mutations in these two genes are yet another means by which downstream PI3K pathway events can be activated.
IGF-1 Signaling Pathway and PTEN Among the many upstream tyrosine kinase receptors that can activate PI3K the insulin receptor family is perhaps the most tightly linked. Among the data forging this link are studies of aging and nutrient response in C elegans where the pi3k pathway is highly conserved and where insulin-like growth factor (IGF) signaling is genetically linked to pten, Akt, and pi3k. In mammalian cells, IGF-1 does indeed signal through this pathway. Data from prospective studies of serum and nutrient risk factors for cancer have linked IGF-1 serum levels to risk for a number of cancers including those of the breast, colon, and prostate.85 Given that germline alterations in PTEN lead to elevated cancer rates in affected individuals an intriguing possibility is that cancer risk and IGF-1 levels are tied to chronic alterations in the levels of PI3K activity in target organs. If so, therapeutic strategies applicable to the treatment of tumors dependent on PI3K signaling may also find a role in prevention strategies.
The signaling outputs of the PI3K pathway, through Akt and other effectors, lead to alterations in multiple cellular processes including cell-cycle regulation, cell-survival, cell adhesion and motility, angiogenesis, glucose homeostasis, and cell size and organ size control. Each is deserving of attention; however, recent developments elucidating connections between PTEN/PI3K/Akt and mTOR signaling make this area worthy of greater detail.
Regulation of the Cell Cycle Progression
Regulation of Cell Survival
Regulation of Cell Spreading and Motility
Regulation of Angiogenesis
Regulation of mTOR (mammalian target of rapamycin) Signaling: A Nutrient Response Pathway Recently, genetic studies in D melanogaster have also placed the gene products (hamartin and tuberin) of the tuberous sclerosis genes (tsc1 and tsc2) in the dTOR pathway. Here, as with dpten, loss-of-function mutations in the drosophilia homologues dtsc1 and dtsc2 lead to increased cell size, proliferation, and deregulated organ size.106 Tuberous sclerosis, like CS and BRRS, is an autosomal dominant disorder characterized by hamartoma formation in a variety of tissues including the brain, skin (not the hair follicle), and kidney leading to a set of common clinical symptoms including seizures, mental retardation, autism, kidney failure, facial angiofibromas, and cardiac rhabdomyomas.107,108 Mutation in either the TSC1 or TSC2 tumor suppressor gene is responsible for both the familial and sporadic forms of this disease. Thus, two hamartoma syndromes, with distinct phenotypes resulting from mutation in different genes (PTEN and TSC genes), are both a result, at least in part, from deregulated activation of the mTOR signaling pathway. Although the biologic bases of these pathologic alterations are not well understood, the molecular connections are becoming more evident (Fig 3). Epistasis studies in D melanogaster have demonstrated that dpten, dtsc1, and dtsc2 act upstream of ds6k (a gene encoding a kinase known as p70S6K in mammalian cells) and while dpten appears to be upstream of dAkt, dtsc1, and dtsc2 are downstream of dAkt.109 Moreover, in various organisms, recent data have shown that the TSC2 gene product is a direct substrate of Akt that is inhibited by such phosphorylation events and thus can modulate PI3K-dependent activation of p70S6K.110,111 Although the precise action of the TSC genes are not known it is clear that they, like PTEN, are negative regulators of signaling through mTOR and in turn p70S6K. The mTOR pathway has two key downstream components germane to the study of human tumors, the ribosomal protein S6, a direct substrate of p70S6K and 4EBP-1, an inhibitor of protein translation. Due to increase in mTOR and in p70S6K activity, both are aberrantly phosphorylated in PTEN-null cells. Thus, while mTOR and p70S6K may serve as targets for antineoplastic agents, S6 and 4EBP-1 may serve as markers of pathway activity in human tumors. Finally, emerging and older data have suggested that specific members of the mTOR pathway, including p70S6K may themselves be targeted for oncogenic activation.112
It is clear that deregulated activation of the PI3K/Akt pathway, achieved through the numerous genetic and epigenetic alterations, contributes substantially to the pathogenesis of a growing list of human cancers. Although direct genetic alteration of kinases (eg, BCR-ABL) in human cancer is one mechanism by which cells may be rendered "kinase" dependent, kinase activation and dependency might also occur through genetic inactivation of kinase regulators such as PTEN. Indeed, emerging data suggests that tumors harboring such alterations likely remain dependent on a persistent PI3K signal for continued proliferation, survival, or migration. Such dependency may point to a substantial therapeutic window for small molecule inhibitors developed to interdict PI3K signal transmission. Thus, there is guarded optimism that successful therapeutics direct against certain kinase elements of the PI3K pathway will be developed. Optimism that is, at least in part, based on the already proven ability to develop relatively specific, small molecule kinase inhibitors, such as imatinib and gefitinib.
Inhibition of PI3K
Inhibition of Akt
Receptor Tyrosine Kinase Inhibitor
Inhibitors of mTOR: Rapamycin and Its Analogs The link between PTEN and mTOR suggested that PTEN-null cells might require mTOR activation for maintenance of aspects of the transformed phenotype including proliferation. Indeed, PTEN-null tumor cell lines, xenografts and tumors in mice appear to have selective sensitivity to rapamycin and CCI-779119,120 raising the possibility that such compounds might have a therapeutic role in patients whose tumors lack PTEN. As described earlier, loss of PTEN function is associated with phosphorylation and activation of Akt, p70S6K, mTOR, and 4E-BP. Thus, analysis of activation of downstream targets of PTEN may identify a broader spectrum of patients responsive to the effect of CCI-779 than would mutation analysis alone. In fact cells transformed by v-Akt or v-PI3K, but not by a host of other oncogenes, are also quite sensitive to rapamycin.121
Clinical data for RAD001 are scant as phase I testing is still in progress. CCI-779 has been administered to patients both orally and intravenously in both phase I and phase II trials. Dose-limiting toxicity (stomatitis, rash, and increased AST) was reached at 100 mg PO daily for 5 days every 2 weeks122 and a maximum tolerated dose for intravenous (IV) administration weekly was not reached in one study at a dose level of 220 mg/m2 123 though dose-limiting hypocalcemia was seen at high doses in another.124 In the initial phase I trials, several patients with renal cell cancer experienced tumor regression,123 a response has been noted in metastatic breast cancer and disease stabilization non–small-cell lung cancer, sarcoma, mesothelioma, and renal cell cancer.124 Adverse effects include rash, mucositis, asthenia, alterations in liver function tests, leukopenia and thrombocytopenias. Phase II clinical trials are underway in glioma (NABTC 0101), prostate, metastatic breast cancer, renal cell carcinoma, lymphoma, melanoma, and small cell lung cancer (ECOG 1500). In 110 patients with renal cell carcinoma the preliminary results of CCI-779 treatment were recently reported. CCI-779 was well tolerated with frequent mild side effects of rash (72%) and mucositis (65%) while the most frequent serious side effects were hyperglycemia and anemia. Here, 5% of patients had partial responses, while a larger fraction had stable disease.125 Similar side effects have been reported in a phase II trial in metastatic breast cancer where in the first 85 evaluable patients, stable disease or partial response for The doses tested in the studies of CCI-779 have generally ranged on the high side 75 to 250 mg IV weekly or 75 mg PO daily (5 days out of 14 days). An essential question is whether such doses exceed the maximally effective bioactive dose, in other words, the minimal dose required to maximally inhibit mTOR. If so, then excessive dosing might lead to side effects unrelated to inhibition of the mTOR pathway (in other words unrelated to the putative therapeutic mechanism). In addition, these studies have yet to report the activation status of the PI3K or mTOR pathways or the status of PTEN in these patients, thus the hypothesis that such tumors are, in humans, hypersensitive to such inhibition remains untested. If the data from animal and cell–based models is indicative of the response of PTEN-null tumors in humans then a reasonable prediction is that lower doses of mTOR inhibitors combined with rigorous patient selection might lead to greater efficacy with lower toxicity. Substantial preclinical data have established the PTEN/PI3K/Akt pathway as a major oncogenic pathway linked to the development of some of the most common human cancers. The future holds great promise for the rapid development of selective novel anticancer agents specifically targeting components of this pathway. Understanding the parameters for patient selection and developing pharmacodynamic markers that allow for the optimizing of drug dose and schedule will likely aid in swinging the balance from toxicity to therapeutic effect.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: William R. Sellers, Novartis, Pharmacia. Received more than $2,000 a year from a company for either of the past two years: William R. Sellers, Novartis, Pharmacia.
We thank J. Guillermo Paez, Charles Sawyers (UCLA), Cyril Benes, and Matthew Sherman (Wyeth Research) for the critical reading of the manuscript.
Supported by National Cancer Institute grants RO1CA85912, PO1CA89021, U01CA84995, and P50CA09038; CaP CURE (W.R.S.); the Damon Runyon Cancer Research Foundation; the Dana-Farber/Novartis Drug Discovery Program; and the Department of Defense Prostate Cancer Research Program grant DAMD17-02-1-0048 (I.S.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, one of the regulatory subunit of PI3K, undergoes mutation that likewise is predicted to render the holoenzyme constitutively active.
3 months was observed in seven patients treated at 75 mg and 10 patients treated at 250 mg IV weekly.
