Subtle variations in Pten dose determine cancer susceptibility

Alimonti, Andrea; Carracedo, Arkaitz; Clohessy, John G.; Trotman, Lloyd C.; Nardella, Caterina; Egia, Ainara; Salmena, Leonardo; Sampieri, Katia; Haveman, William J.; Brogi, Edi; Richardson, Andrea L.; Zhang, Jiangwen; Pandolfi, Pier Paolo

doi:10.1038/ng.556

Cited by 505 publications

(481 citation statements)

References 21 publications

(33 reference statements)

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“…A similar role was attributed to PTEN in other types of cancers. 9 Subsequently, we explored the effect of siRNA PTEN silencing on KIT downstream signaling in vitro using GIST cell lines. Noteworthy, in both imatinib-sensitive and imatinib-resistant GIST cells, PTEN silencing resulted in overactivation of both, AKT and MAPK; the latter being exceptionally hyper-phosphorylated in imatinib-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

“…8 In human malignancies, PTEN inactivation or insufficiency constitutively activates this pathway. 9 Thereby, GIST patients with PTEN deficiency could benefit from alternative therapies targeting the PI3K/AKT/mTOR pathway. In line with this concept, an oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) has been tested in combination with imatinib in phase I-II clinical trials for patients with imatinib-resistant GIST, pointing to a potential therapeutic benefit of the combined administration.…”

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confidence: 99%

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Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naı¨ve and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naı¨ve vs imatinib-resistant tumors (9% vs 39%, Po0.001). Neither PTEN mutations nor PTEN promoter hyper-methylation were found. By immunohistochemistry, PTEN depletion was clearly related to GIST progression. Low PTEN protein expression was common (50%) and often paralleled with total immunonegativity in imatinib-resistant tumors. The abnormal PTEN protein expression correlated with PTEN loss at the genomic level (P ¼ 0.001). In addition, the effect of small interfering RNA (siRNA) PTEN knockdown on KIT signaling was examined in GIST-T1 and GIST430 cell lines, in the absence or presence of a dual PI3K/mTOR inhibitor NVP-BEZ235, alone or in combination with imatinib. In both cell lines, siRNA silencing of PTEN resulted in the substantial upregulation of PI3K-AKT and MAPK pathways. The MAPK hyperactivation was further potentiated by NVP-BEZ235 in the imatinib-sensitive GIST-T1 cells; yet, this effect was counteracted efficiently by combined treatment. In the imatinib-resistant GIST430 cells, neither NVP-BEZ235 alone or in combination with imatinib yielded sufficient inhibition of hyper-phosphorylated MAPK and downstream intermediate S6 protein. In conclusion, depleted PTEN expression associated with mono-allelic PTEN loss occurs frequently in imatinib-resistant GIST and might serve as a biomarker for stratifying patients for optimal treatment. In vitro, the PTEN insufficiency leads to hyperactivation of AKT and MAPK pathways in tumor cells. Novel therapies targeting multiple components of the integrated KIT receptor signaling pathways in imatinibresistant GIST warrant further studies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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“…PTEN was chosen as a candidate because (i) it is a shared target of miR-19 and miR-20a; (ii) small modifications of PTEN expression have important functional consequences (Alimonti et al, 2010), suggesting that deregulation of the micro-RNA level of regulation could be sufficient for a role in CoGAM induction and (iii) PTEN overexpression is known to inhibit growth of MCF-7 cells through induction of a G1 arrest (Weng et al, 1999). Clearly, complementation of Drosha knockdown by PTEN knockdown is only partial, and less efficient than miR-19 or miR-20 complementation.…”

Section: Discussionmentioning

confidence: 99%

Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

2011

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“…[70][71][72] With regard to SDH-related oncogenesis, it has been suggested that the tumor phenotypes could be affected by the size of SDH deletions because they can encompass closely located TSGs and compromise their function, which could lead to unusual phenotypes. 73,74 In addition, some research suggests that germ-line and somatic interactions could account for the clinical variability observed among carriers of an identical SDH germ-line mutation, including those within the same family.…”

Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

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Subtle variations in Pten dose determine cancer susceptibility

Cited by 505 publications

References 21 publications

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

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