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Key Points The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, apoptosis and cytoskeletal rearrangement. PI3Ks are heterodimeric lipid kinases that are composed of a regulatory and catalytic subunit that are encoded by different genes. The genes that encode the regulatory domains are also subject to differential splicing. Class IA PI3Ks are activated by receptor tyrosine kinases, and deregulation of their function has been implicated in several human cancers. One of the main functions of PI3K is to synthesize the second messenger PtdIns(3,4,5)P3 (PIP 3 ) from PtdIns(4,5)P 2 (PIP 2 ). AKT — a serine/threonine kinase that has a wide range of substrates — is activated by recruitment to the plasma membrane through direct contact of its pleckstrin-homology (PH) domain with PIP 3 , and phosphorylation at Thr308 and Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase PDK1, whereas Ser473 is phosphorylated by a molecularly unidentified kinase, often termed PDK2. AKT acts downstream of PI3K to regulate many biological processes, such as proliferation, apoptosis and growth, but other signalling pathways are also known to be regulated by PI3K activity and might be involved in PI3K-mediated tumorigenesis. The available clinical evidence of PI3K-pathway deregulation in various cancers and the identification of downstream kinases that are involved in mediating the effects of PI3K (AKT, mTOR, PDK1 and ILK) provide potential targets for the development of small-molecule therapies. The importance of lipid–protein interaction domains (such as the PH domains of AKT and PDK1) for the activation of PI3K targets provides another potential strategy for developing targeted therapies. One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K). This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression. Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.

Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.

The serine/threonine kinase AKT is a critical effector of the phosphoinositide 3-kinase (PI3K) signaling cascade and has a pivotal role in cell growth, proliferation, survival, and metabolism. AKT is one of the most commonly activated pathways in human cancer and dysregulation of AKT-dependent pathways is associated with the development and maintenance of a range of solid tumors. There are multiple small-molecule inhibitors targeting different components of the PI3K/AKT pathway currently at various stages of clinical development, in addition to new combination strategies aiming to boost the therapeutic efficacy of these drugs. Correlative and translational studies have been undertaken in the context of clinical trials investigating AKT inhibitors, however the identification of predictive biomarkers of response and resistance to AKT inhibition remains an unmet need. In this review, we discuss the biological function and activation of AKT, discuss its contribution to tumor development and progression, and review the efficacy and toxicity data from clinical trials, including both AKT inhibitor monotherapy and combination strategies with other agents. We also discuss the promise and challenges associated with the development of AKT inhibitors and associated predictive biomarkers of response and resistance.

The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra‐physiological levels of phospho‐tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry‐based phospho‐proteomics, we show that glucose withdrawal initiates a unique signature of phospho‐tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal‐induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS‐mediated cell death. Taken together, these findings illustrate the systems‐level cross‐talk between metabolism and signaling in the maintenance of cancer cell homeostasis. In cancer cells dependent upon glucose for survival, glucose withdrawal activates a positive feedback loop involving reactive oxygen species (ROS), ROS‐mediated inhibition of tyrosine phosphatases, and tyrosine kinase signaling. This loop amplifies ROS to toxic levels, resulting in cell death. Synopsis In cancer cells dependent upon glucose for survival, glucose withdrawal activates a positive feedback loop involving reactive oxygen species (ROS), ROS‐mediated inhibition of tyrosine phosphatases, and tyrosine kinase signaling. This loop amplifies ROS to toxic levels, resulting in cell death. In cancer cell lines dependent on glucose for survival, glucose withdrawal induces supra‐physiological levels of phospho‐tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Unbiased, mass spectrometry‐based phospho‐tyrosine profiling demonstrates that glucose withdrawal induces a unique signature of phospho‐tyrosine signaling associated with focal adhesions. The glucose withdrawal‐induced phospho‐tyrosine signature results from a positive feedback loop in which reactive oxygen species (ROS) oxidize and inhibit protein tyrosine phosphatases, causing increased tyrosine kinase signaling, thereby inducing further ROS generation until cells undergo ROS‐mediated cell death. The glucose withdrawal‐initiated positive feedback loop illustrates the complex, systems‐level integration of metabolism and tyrosine kinase signaling in cancer cell homeostasis.

Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer. Mutation of the gene PARK2 , which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease 1 , 2 , 3 . In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2 , a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving [almost equal to]35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.

Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.

A small proportion of glioblastomas respond to gefitinib or erlotinib (tyrosine kinase inhibitors). Some of these responsive tumors have a mutant variant of the epidermal growth factor receptor (EGFR), and some unresponsive tumors lack PTEN, a regulator of the pathway that a mutant EGFR activates. The simultaneous presence in glioblastoma cells of mutant EGFR and PTEN was associated with responsiveness to tyrosine kinase inhibitors. The simultaneous presence in glioblastoma cells of mutant EGFR and PTEN was associated with responsiveness to tyrosine kinase inhibitors. Tyrosine kinases are key regulators of intracellular signaling. 1 , 2 Overexpressed or mutated tyrosine kinases occur in many types of cancer and contribute to the development and progression of tumors. 3 – 5 The dependence of tumor cells on persistently activated tyrosine kinases may render tumors susceptible to inhibitors of these kinases. 3 – 7 The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is a target for such inhibitors because it is amplified, mutated, or both in a number of neoplasms. 8 A small subgroup of patients with lung cancer have a response to EGFR inhibitors, 9 – 11 and mutations in the EGFR kinase domain . . .

The serine–threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer. To maintain a healthy body, the ability of our cells to survive and divide is normally strictly controlled. If any cells manage to escape these restrictions, they may rapidly divide and form tumors, which can lead to cancer. A protein called AKT can encourage cells to survive and divide, and in healthy cells it is only allowed to be active at specific times. However, in many cancer cells, the genes that make and control AKT activity can be altered by mutations, which can result in AKT being active at the wrong times. Part of the AKT protein acts as an enzyme called a kinase and adds chemical groups called phosphates to other proteins. The phosphate groups can activate or deactivate these proteins to control cell survival and cell division. However, there are other sections to the AKT protein and it is not clear how they are involved in this protein's activity. In this study, Vivanco et al. show that AKT has another role in cell survival that does not depend on its kinase. The experiments show that even when the kinase part of the protein is missing, AKT can help cancer cells to survive drug treatments and external conditions that would normally kill them. This role requires another section of the protein called the PH-domain. There are several chemicals—called inhibitors—that can stop AKT from working properly, and they have the potential to be used to treat some types of cancer. These inhibitors work in different ways: some were able to block the activity of the kinase, but others inhibited AKT by binding to other parts of the protein. Therefore, to develop AKT inhibitors into effective drugs, it will be important to know precisely what role the protein plays in different types of cancers.

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway. The epidermal growth factor receptor (EGFR) signalling is regulated at multiple levels. Here the authors show that the importin RanBP6 acts as a tumor suppressor in Glioblastoma and  regulates EGFR signalling through promoting translocation of STAT3 to the nuclei and repressing EGFR transcription.