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The role of PTEN signaling perturbations in cancer and in targeted therapy

Abstract

The PTEN tumor suppressor was discovered by its homozygous deletion and other mutations in cancer. Since then, PTEN has been shown to be a non-redundant, evolutionarily conserved phosphatase whose function affects diverse cellular progresses such as cell cycle progression, cell proliferation, chemotaxis, apoptosis, aging, muscle contractility, DNA damage response, angiogenesis and cell polarity. In accordance with its ability to influence multiple crucial cellular processes, PTEN has a major role in the pathogenesis of numerous diseases such as diabetes, autism and almost every cancer examined. This review will discuss the diverse ways in which PTEN signaling is modified in cancer, and how these changes correlate with and might possibly affect the action of targeted chemotherapy.

Introduction

The PTEN (Phosphatase and Tensin homolog deleted from chromosome ten) tumor suppressor was identified by homozygous deletion mapping of the human chromosome 10q23 in cancer (Li et al., 1997; Steck et al., 1997). Sequencing of the PTEN gene in tumors found it to be one of the most commonly mutated tumor suppressors in human malignancies (Dahia et al., 1997; Rasheed et al., 1997; Tashiro et al., 1997; Wang et al., 1997, 1998; Cairns et al., 1998; Duerr et al., 1998; Shao et al., 1998). The hereditary loss of PTEN leads to numerous autosomal dominant disorders: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome and Proteus-like syndrome, which are characterized by the presence of developmental defects, benign hamartomas and an increased risk of cancer (Liaw et al., 1997; Marsh et al., 1997; Zhou et al., 2000, 2001). In addition to PTEN mutations, a host of other genetic alterations in the PTEN pathway have emerged as common mechanisms that hinder or bypass PTEN function in tumors (Samuels et al., 2004; Saal et al., 2005; Carpten et al., 2007; Palomero et al., 2007; Wiencke et al., 2007; Yang et al., 2008). When taking these new regulatory modes into account, it appears that PTEN signaling is almost universally altered in cancer. This review highlights signaling changes that result from modifications in the PTEN/PI3K network in tumors and discusses the correlation between and functional significance of PTEN/PI3K pathway status and targeted chemotherapy efficacy.

The role of PTEN as a tumor suppressor has been unraveled by genetic and biochemical studies, as well as work in model organisms. Molecularly, the PTEN protein is a dual-specificity phosphatase that is capable of removing phosphates from protein and lipid substrates (Maehama and Dixon, 1998; Myers et al., 1998). The primary target of PTEN in cancer is the lipid second messenger phosphatidylinositol (3,4,5) tri-phosphate (PIP3) (Myers et al., 1998). PTEN removes the D3 phosphate from PIP3 producing phosphatidylinositol (4,5) bi-phosphate (PIP2). Resting cells normally have low levels of PIP3, which are increased upon growth factor signaling. The loss of PTEN leads to constitutively high levels of PIP3, which mimics growth factor stimulation (Stambolic et al., 1998). PIP3 induction leads to cell cycle progression, enhanced survival and increased cell size (Auger et al., 1989; Serunian et al., 1990). On the contrary, the overexpression of PTEN leads to cell cycle arrest, apoptosis and small cell size (Furnari et al., 1997, 1998; Stokoe et al., 1997; Li et al., 1998; Ramaswamy et al., 1999). Hence, the molecular mechanisms ascribed to PTEN are consistent with its role as a tumor suppressor.

Once thought to be a constitutively active phosphatase, potentially regulatory post-translational modifications of PTEN have steadily emerged over the past few years. These alterations include phosphorylation, acetylation, oxidation, ubiquitination and caspase cleavage (Vazquez et al., 2000, 2001; Tolkacheva et al., 2001; Lee et al., 2002; Das et al., 2003; Leslie et al., 2003; Torres et al., 2003; Kim et al., 2005; Okumura et al., 2006; Trotman et al., 2007; Wang et al., 2007). These modifications alter the level of phosphatase activity, affect the incorporation of PTEN into higher molecular weight complexes, direct subcellular localization, and influence protein stability. Investigating the contributions of these modifications to the loss of PTEN phenotype in cancer is essential. Ideally, the molecular mechanisms that regulate PTEN could be harnessed to restore its tumor suppressor activities in the future.

Mouse models further illustrate the importance of PTEN in cancer. The homozygous deletion of PTEN is embryonic lethal with developmental defects in the mesoderm, endoderm and ectoderm (Di Cristofano et al., 1998; Podsypanina et al., 1999). The heterozygous loss of PTEN leads to numerous neoplasms found in the prostate, thyroid, colon, lymphatic system, mammary gland and endometrium (Di Cristofano et al., 1998; Podsypanina et al., 1999). The haploinsufficiency of PTEN in mice also cooperates with the expression of oncogenes and the loss of additional tumor suppressors to unveil novel genetic interactions (Di Cristofano et al., 2001; Kim et al., 2002; You et al., 2002; Ma et al., 2005b; Yao et al., 2008). One such interaction was recently published in which the deletion of PTEN (heterozygous or homozygous) in combination with the expression of an activated ErbB2 (Neu, HER2) allele resulted in the accelerated formation of breast cancer (Dourdin et al., 2008). The invaluable information emerging from PTEN mouse models points to novel signaling mechanisms involving PTEN, the understanding of which is critical when classifying and treating cancer.

Throughout evolution, the PTEN gene has been well conserved. In Dictyostelium, PTEN participates in the sensing of chemoattractants, the temporal and spatial regulation of chemotaxis, the regulation of cytokinesis, and the regulation of basic cellular motility (Iijima and Devreotes, 2002; Iijima et al., 2002; Janetopoulos et al., 2005; Sasaki et al., 2007). In C. elegans the PTEN homolog (DAF-18) regulates aging and dauer formation by opposing AGE-1 (PI3K) (Ogg and Ruvkun, 1998). Recently, DAF-18 has also been shown to regulate nutrient-dependent cell cycle arrest in C. elegans, (Fukuyama et al., 2006). The roles of PTEN in Drosophila are broader than those described in worms. The Drosophila DPTEN gene affects lifespan when expressed from the fat body of the head (Hwangbo et al., 2004). In addition to this, DPTEN also regulates proliferation, cell size and cytoskeletal remodeling (Goberdhan et al., 1999). The roles of PTEN in mammalian systems are far reaching as it profoundly affects development, metabolism and tumor progression (Di Cristofano et al., 1998; Stambolic et al., 1998; Podsypanina et al., 1999; Accili and Arden, 2004; Kitamura et al., 2005).

Overview of the PTEN network

The PTEN network encompasses signals from growth factor receptors on the cell surface to transcription factors that act in the nucleus, complete with interconnections to other tumor suppressor and oncogenic signaling pathways. A simple schematic view of the PTEN pathway is shown in Figure 1. At the plasma membrane, ligand-bound growth factor receptor tyrosine kinases and Ras can activate phosphatidylinositol 3 kinase (PI3K), a heterodimeric kinase that phosphorylates PIP2 to produce PIP3, thereby directly antagonizing PTEN (Klinghoffer et al., 1996). The second messenger PIP3 binds to a subset of pleckstrin homology domain-containing proteins, enabling the plasma membrane recruitment and activation of target proteins (Frech et al., 1997; Klarlund et al., 1997). Intriguingly, PIP3 is also found in the nucleus, along with PTEN and other pathway components, revealing a more complex view of the PTEN network (Tanaka et al., 1999; Liu et al., 2005a, 2005b; Deleris et al., 2006; Gil et al., 2006; Li et al., 2006; Lindsay et al., 2006; Trotman et al., 2006, 2007; Baker, 2007; Shen et al., 2007; Chang et al., 2008).

Figure 1
figure1

The Phosphatase and Tensin homolog deleted from chromosome ten (PTEN)/phosphatidylinositol 3 kinase (PI3K) network regulates many facets of cancer biology. Pictured is a simplistic schematic representation of the PTEN/PI3K pathway in cancer. Lines represent direct or indirect activation (arrow head) or inactivation (blunt end) by various signaling molecules. In essence, certain growth factor receptor tyrosine kinases and Ras activate PI3K, leading to an increase in the cellular levels of phosphatidylinositol 3,4,5 tri-phosphate (PIP3). PIP3 binds to and activates a subset of pleckstrin homology domain-containing proteins including the protein kinases PDK1 and AKT. These kinases in turn regulate many critical processes involved in cancer such as cell cycle progression, apoptosis and cellular growth/ translation. PTEN acts as a critical negative regulator of PI3K signaling by removing the D3 phosphate from PIP3 to produce phosphatidylinositol 4,5 bi-phosphate (PIP2). For simplicity, this figure predominantly pictures the membrane/cytoplasmic localization of certain PTEN/PI3K pathway components, even though many of these molecules are also known to reside and function in the nucleus.

PI3K signaling induces a diverse array of cancer-promoting events including the regulation of the protein kinases PDK1 and AKT, which directly bind to and are activated by PIP3 (Alessi et al., 1997; Currie et al., 1999). PDK1 (3-phosphoinositide dependent protein kinase-1) is encoded by a single gene and is a member of the AGC kinase family (Alessi et al., 1997). PDK1 phosphorylates numerous target proteins within the T loop, enabling activation. The AKT serine/threonine kinase phosphorylates substrates containing the minimal recognition sequence: R-X-R-X-X-S/T (Alessi et al., 1996). AKT has three isoforms, each of which is encoded by a different gene (AKT1, AKT2 and AKT3). Upon PIP3 binding, PDK1 induces AKT kinase activity 30-fold by phosphorylating it on residue T308 (Alessi et al., 1997). AKT, in turn, phosphorylates a plethora of targets to activate the cell cycle, prevent apoptosis and trigger cellular growth (Manning and Cantley, 2007). Compound mouse genetics underscore the importance of AKT and PDK1 as mediators of the cancer phenotype found in PTEN heterozygous mice. Specifically, the loss of AKT1 suppresses tumor formation in PTEN heterozygous mice (Chen et al., 2006). Similarly, the hypomorphic expression of PDK1 (levels that are 80–90% reduced compared with normal) inhibits tumor formation in PTEN heterozygous mice (Bayascas et al., 2005). These data validate AKT1 and PDK1 as essential for tumor development resulting from the diminishment of PTEN.

AKT is one of the most prominent mediators of PI3K signaling in cancer. Over 20 direct AKT targets have been identified, including components involved in apoptosis, cell cycle progression, cell growth and genetic stability. AKT blocks the action of numerous transcription factors, including the FOXO family members (FOXO1, FOXO3 and FOXO4) as well as PAR-4, to inhibit apoptosis (Nakamura et al., 2000; Accili and Arden, 2004; Goswami et al., 2005). The pro-apoptotic protein BAD is also inhibited by AKT (Datta et al., 1997). Several negative regulators of the cell cycle are subject to inactivation by AKT including p27, GSK3B and the FOXO transcription factors (Cross et al., 1995; Liang et al., 2002). AKT also has a pronounced effect on cellular growth by activating the mTOR kinase. In particular, AKT phosphorylates and inactivates the RHEB-GAP (GTPase-activating protein) TSC2 (Manning et al., 2002; Tee et al., 2002, 2003; Zhang et al., 2003a, 2003b). As a result, phosphorylated TSC2 is no longer able to interact with its functional partner TSC1, leading to a loss of protein stability and activity (Potter et al., 2002). The concomitant increase in RHEB-GTP activates mTOR when it resides in a multifunctional complex termed mTORC1 (Long et al., 2005). The rapamycin-sensitive mTORC1 complex activates p70S6K (to increase translation) and inhibits 4E-BP1 (to block translation initiation inhibition) (Fingar et al., 2002). The mTOR kinase also exists in another complex termed mTORC2 that phosphorylates AKT on residue S473, enhancing kinase activity (Sarbassov et al., 2005). The action of AKT also directly affects genetic stability in cancer by targeting the CHK1 kinase to the cytoplasm, leading to DNA double-strand breaks (Puc and Parsons, 2005; Puc et al., 2005). All things considered, AKT is a node in the PTEN pathway by virtue of its ability to regulate a substantial number of targets of significance in cancer.

In addition to AKT, the JNK kinase has also recently been implicated as a PI3K effector in cancer. Intriguingly, JNK can promote apoptosis in response to environmental stress triggers or it can aid in cellular transformation in concert with certain oncogenes such as BCR-ABL (Raitano et al., 1995; Xia et al., 1995). The loss of PTEN increases EGF-induced phospho-JNK by multiple mechanisms in a context-dependent manner (Vivanco et al., 2007). AKT is not required for JNK activation. Strikingly, the combination of AKT and JNK synergistically transforms NIH3T3 cells and astrocytes, suggesting that these PI3K targets impart independent transforming outputs (Vivanco et al., 2007). Future studies of the roles of JNK as well as other PI3K targets in mediating cancer progression will be invaluable.

The PTEN network does not function in isolation; rather, it interconnects extensively with other tumor suppressor pathways and with oncogenic signaling pathways (such as those involving p53 and Ras). Not only do PTEN and p53 participate in many of the same cellular processes, they also physically interact and regulate each other. The physical association between p53 and PTEN affects the p53 acetylation state and its ability to bind DNA (Freeman et al., 2003; Li et al., 2006; Chang et al., 2008). The p53 transcription factor also binds to the PTEN promoter and transactivates PTEN gene expression (Stambolic et al., 2001). Ras connects with the PTEN pathway by activating PI3K and by regulating some of the same targets as PI3K, such as BAD and TSC2 (Zha et al., 1996; Datta et al., 1997; Fang et al., 1999; Ma et al., 2005a; Gupta et al., 2007). In addition, activated Ras leads to a loss of PTEN expression through c-Jun-mediated events (Vasudevan et al., 2007). The ability of PTEN signaling to integrate with p53 and Ras exemplifies the many interconnections between PTEN and other tumor suppressor and oncogenic signaling networks.

Perturbations of PTEN signaling in cancer

The PTEN tumor suppressor pathway is almost universally compromised in cancer. Certain nodes within the pathway are recurrent targets for alteration. These include changes in the status and regulation of PTEN as well as PI3K. Upstream of PTEN/PI3K signaling, growth factor receptors are amplified and activated by mutations in tumors. Additionally, effectors of PTEN and PI3K are also directly modified in particular cancers, albeit at low frequencies.

The PTEN gene located on chromosome 10q23 is commonly mutated or otherwise downregulated in a broad range of cancers (Li et al., 1997; Steck et al., 1997). Aberrant PTEN signaling is associated with metastasis and poor prognosis in breast and other cancers (Saal et al., 2007). Genetic alterations of the PTEN gene range from point mutations (encoding mostly unstable and/or catalytically inactive proteins) to large chromosomal deletions (Li et al., 1997; Steck et al., 1997; Georgescu et al., 1999, 2000). Among these mutations are structural rearrangements within the PTEN gene (intragenic inversions, insertions, deletions and duplications known as gross PTEN mutations) that occur in BRCA1-associated basal-like breast cancer (Saal et al., 2008). PTEN mutation frequencies affecting both alleles in various cancers are: endometrial (50%), glioblastoma (30%), prostate (10%), and breast (5%) (Cairns et al., 1997, 1998; Li et al., 1997; Steck et al., 1997; Tashiro et al., 1997; Wang et al., 1997; Chiariello et al., 1998; Duerr et al., 1998; Lin et al., 1998; Shao et al., 1998; Ali et al., 1999; Zhou et al., 2002; Saal et al., 2005). The monoalleleic loss of PTEN is regularly observed in a considerable fraction of malignancies at the following frequencies: glioma (75%), breast (40–50%), colon (20%), lung (37%), prostate (42%) (Teng et al., 1997; Bose et al., 1998; Feilotter et al., 1998; Lin et al., 1998; Rubin et al., 2000). Aside from the genetic modification of PTEN, its expression is also frequently diminished at the transcriptional/translational level. DNA methylation, transcriptional repression and micro-RNA-directed mRNA degradation and translational disruption appear to reduce PTEN expression in numerous cancers (Wiencke et al., 2007; Yang et al., 2008). One recent study identified a mechanism to explain the common deficiency of PTEN in leukemia. In particular, NOTCH1 activation (by translocation or activating mutation) was found to reduce PTEN gene expression in human T-ALL through the transcriptional repressor HES1 (Palomero et al., 2007). Collectively, it is becoming increasingly clear that the loss of PTEN in cancer is extremely common and is accomplished in many different ways.

The PTEN antagonist PI3K is comprised of a regulatory p85 subunit and a catalytic p110 subunit. The p85 subunit binds to and negatively regulates the p110 subunit until the complex is engaged and activated by growth factor signaling. Upon activation, the p85 subunit remains bound to the catalytic subunit, but it is thought to change in conformation to properly position the kinase to an active form (Skolnik et al., 1991). In addition, Ras directly binds to and activates the catalytic subunit of PI3K (Gupta et al., 2007). As PI3K directly opposes PTEN, it is not surprising that the gene encoding the catalytic subunit p110α, PIK3CA, frequently harbors activating mutations in cancer including gastric (25%) colon (32%), breast (25%) and lung cancer (4%) (Samuels et al., 2004; Saal et al., 2005). The catalytic subunit of PI3Kα is also amplified in ovarian cancer (Campbell et al., 2004). The mutations identified in PIK3CA cluster to hotspots within the helical and kinase domains (Samuels et al., 2004). These mutants confer constitutively high levels of phospho-AKT on the residues T308 and S473, which leads to an increase in the phosphorlyation of the FOXO transcription factors (FOXO1 and FOXO3), but not to an increase in the regulation of other AKT targets, such as TSC2 and GSK3B (Samuels et al., 2005). These surprising results suggest that activating alleles of PI3K are not exactly equivalent to the loss of PTEN, because they only regulate a subset of AKT targets. Furthermore, the helical and kinase domain mutants both have increased kinase activity, but are activated by different mechanisms. Studies performed in chicken embryonic fibroblasts demonstrate that the helical domain mutations (E542K and E545K) require interaction with RAS-GTP, but not with p85 (Zhao and Vogt, 2008). In essence, the helical mutants appear to position the kinase in a way such that it is no longer subject to the negative regulation by p85, but the catalytic domain still requires Ras for activation. Conversely, the kinase domain mutant H1047R acts independently of RAS-GTP binding, but requires p85 for activation. The helical and kinase domain double mutants synergistically activate downstream signaling events and increase cellular transformation, further demonstrating that the individual (helical and kinase domain) mutants operate by different mechanisms (Zhao and Vogt, 2008). All told, the recurrent genetic activation of PI3K is another way in which the PTEN pathway can be disturbed in cancer. Interestingly, studies show that these mutants are activated by different mechanisms and appear to alter only subsets of AKT signaling (Samuels et al., 2005; Zhao and Vogt, 2008).

Upstream regulators of the PTEN/PI3K pathway are also modified in cancer, such as growth factor receptors and Ras. Specifically, activating mutations and gene amplifications of EGFR and HER2 are found in ovarian, breast and other cancers (Kokubo et al., 2005; Moasser, 2007; Vermeij et al., 2008). Particular combinations of growth factor receptor complexes (such as HER2/HER3 and EGFR/GAB1) are able to activate PI3K in a context-dependent manner (Wallasch et al., 1995; Laffargue et al., 1999). In addition, the frequent mutation of K-Ras in cancer leads to, among other things, aberrant PI3K activation (Pao et al., 2005; Lievre et al., 2006; Gupta et al., 2007). Therefore, these mechanisms also need to be considered as potentially important influences on PI3K pathway signaling in cancer.

The activation of AKT in cancer is oftentimes accomplished by the loss of PTEN or the activation of PI3K. However, the AKT2 gene is amplified in about 10% of ovarian cancers and 3% of breast cancers (Bellacosa et al., 1995; Parsons et al., 2005). A recent study has also reported that AKT1 is mutated within the Pleckstrin Homology Domain (E17K) in 8% of breast, 6% of colorectal and 2% of ovarian cancers that were examined (Carpten et al., 2007). This mutation alters the conformation of the Pleckstrin homology domain and increases kinase activity in vitro and in NIH3T3 cells. Furthermore, the E17K mutation increases membrane localization and transforms Rat1 cells in culture (Carpten et al., 2007). These results further demonstrate the importance of AKT as a PI3K effector in cancer.

Effectors of PTEN are less commonly mutated in cancer. A portion of the FOXO1 gene is fused to either PAX3 or PAX7 in a striking 85% of rhabdomyosarcomas (Barr, 2001; Sorensen et al., 2002). These translocations are also commonly amplified. Studies suggest that the loss of the wild-type allele of FOXO1 is an important part of the pathogenicity associated with these translocations, because the expression of the PAX3–FOXO1 fusion alone is not sufficient to induce tumors in transgenic or murine knock-in models (Lagutina et al., 2002; Keller et al., 2004). Aside from the translocations, the FOXO1 gene is not found to be mutated in cancer (Catalog of Somatic Mutations in Cancer, http://www.sanger.ac.uk/genetics/CGP/cosmic/).

Alterations of the PTEN pathway associate with poor response and presumably affect targeted chemotherapy efficacy

Rationally designed targeted chemotherapy aims to specifically disrupt the action of particular oncogenic signaling pathways, thereby deterring cancer progression. Recently, the activation of PI3K pathway has been shown to significantly correlate with the lack of efficacy of several targeted therapies including trastuzumab, which targets HER2/ErbB2, as well as with getfitinib and cetuximab, both of which target EGFR (Nagata et al., 2004; Kokubo et al., 2005; Berns et al., 2007; Frattini et al., 2007; Jhawer et al., 2008). Using stringent criteria for the definition of PTEN loss, Nagata et al. (2004) found that there was a significantly worse response to trastuzumab (in combination with taxane) in PTEN negative tumors. Berns et al. (2007) expanded on this concept by showing that PI3K pathway activation in general (by either the loss of PTEN or by the presence of a gain of function mutation in PI3K) correlates with a poor response to trastuzumab. In a similar manner, the general activation of the PI3K pathway (by PTEN loss or PI3K mutation) in colon cancer cell lines predicts lack of response to cetuximab (Frattini et al., 2007; Jhawer et al., 2008). A reduction in PTEN expression is also associated with gefitinib resistance (Kokubo et al., 2005). Interestingly K-Ras mutations, which are known to activate PI3K, are also associated with poor outcome after certuximab treatment (Lievre et al., 2006). These results show that the status of the PTEN/PI3K pathway is significantly correlated with poor outcome from targeted therapy treatment. The signaling mechanisms responsible for the requirement of PTEN in targeted therapy efficacy are currently under rigorous investigation.

A number of models have already been proposed to explain the role of PTEN signaling in determining the efficacy of targeted chemotherapy. Nagata et al. (2004) argue that, at least in part, PTEN is activated by trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of ErbB2 (Neu/HER2). Mechanistically, the ErbB2 receptor binds to and activates the tyrosine kinase SRC that in turn phosphorylates and inactivates PTEN. Trastuzumab blocks SRC activation by ErbB2, which leads to PTEN membrane association and a rapid reduction in phospho-AKT. The ability of trastuzumab to activate PTEN through SRC inhibition occurs within 1 h of treatment. However, prolonged exposure to trastuzumab (>20 h) leads to a loss in ErbB2 expression, dephosphorylation and receptor internalization. The effect of PTEN in these later signaling events could also prove to be significant. In support of this concept, the expression of PTEN increases trastuzumab response in cell viability assays where BT474 cells are treated for several days and xenograft models in which mice were treated for weeks (Nagata et al., 2004). Collectively, it appears that numerous mechanisms, including one in which PTEN is directly activated, are employed by trastuzumab to block ErbB2 signaling.

An altogether different mechanism is proposed for the necessity of PTEN signaling in combination with getfitinib, a small molecule inhibitor of EGFR. She et al. (2005) propose that, instead of acting directly downstream of the targeted therapy, PTEN acts in parallel. Numerous mediators of PTEN are subject to inactivation by both Ras and PI3K signaling. The regulation of the pro-apoptotic BAD protein exemplifies this circumstance. Activated Ras induces MAPK to phorsphorylate BAD on S112, whereas PI3K activates AKT, which in turn phosphorylates BAD on S136. It is known that either of these phosphorylation events abrogates BAD function (Zha et al., 1996; Datta et al., 1997). Therefore, two steps must be taken to activate BAD: PTEN needs to inactivate AKT and gefitinib needs to block Ras to obtain unphosphorylated, active BAD, to induce apoptosis. The logic follows that when PTEN is inactivated in tumors, the function of BAD is constitutively hindered by S136 phosphorylation and therefore, getfitinib treatment becomes unable to activate apoptosis.

The numerous modes of PTEN pathway inactivation lead to a complex array of considerations for employing targeted chemotherapy. Each alteration confers a characteristic signaling environment that has its own constraints and interactions with other molecules. For example, a cancer with a mutant form of PI3K might not affect every AKT target (as illustrated in the cell lines HCT116 and DLD1). Therefore, although certain FOXO transcription factors are rendered inactive, other targets such as TSC2, GSK3B, and potentially BAD are possibly still functional. Similarly, the activating mutations found in AKT would only exert effects on a sector of PI3K signaling. Presumably, the loss of PTEN is the most common change in the pathway, because in this scenario targets are uniformly affected. It is worth mentioning that the response to trastuzumab is poor in the presence of either the loss of PTEN or activating mutations in PI3K. Therefore, even though the precise repertoire of signaling outputs differ among PTEN pathway alterations, the most critical events may be consistently changed. Nevertheless, when designing a therapeutic regimen, one might need to consider that not all changes within the PTEN/PI3K pathway are equivalent. In addition to this, it appears that PTEN pathway status affects targeted therapy efficacy in different ways depending on the drug as well as on the context. In the case of trastuzumab, PTEN can be directly activated by the drug whereas with getfitinib treatment, PTEN was shown to serve in parallel to the drug to activate target proteins. Elucidating the mechanisms responsible for the requirement of PTEN in combination with targeted therapies is a critical area for future research.

Conclusion

The PTEN tumor suppressor has far reaching effects in cancer biology, such as halting proliferation and cell cycle progression, as well as inducing apoptosis. In the field of cancer research, the model of the PTEN network is continually evolving, with interconnections to many other tumor suppressor and oncogenic pathways being constantly unraveled. The PTEN network is almost universally modified in cancer by an increasing number of diverse mechanisms. The different modes of PTEN loss in cancer lead to distinctive changes in signaling that are not always equivalent. Rather, each mode of PTEN pathway modification leads to a specific signaling environment that needs to be considered when classifying and treating cancer. The full extent of the consequences induced by PTEN/PI3K signaling changes is not fully known, but remains an exciting area for future research. It is already established that the PTEN/PI3K status correlates with the efficacy of certain targeted chemotherapies. Different models have been put forth to explain the requirement of PTEN for the effectiveness of certain targeted therapies. Specifically, PTEN can act either directly with or in parallel to particular therapies. Future work on the precise mechanisms encompassing the action of the PTEN network and targeted chemotherapies will be highly informative.

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Acknowledgements

We thank the members of the Parsons Laboratory for the critical reading of this paper. MK received support from the DOD (PC050068). RP received support from the Avon Foundation, the Octoberwoman Foundation, and the NCI (Grants CA097403 and CA082783).

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Correspondence to R Parsons.

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Keniry, M., Parsons, R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27, 5477–5485 (2008). https://doi.org/10.1038/onc.2008.248

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Keywords

  • PTEN
  • PI3K
  • AKT
  • targeted chemotherapy

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