PI3 Kinase Pathway Mutations in Human Cancers

Gray, Joe W.

doi:10.1001/jamaoncol.2016.0875

Cited by 9 publications

(8 citation statements)

References 70 publications

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“…IGF-1R has crosstalk with EGFR and produces tumour resistance to EGFR inhibitors. Various inhibitors could inhibit RAS signalling pathway molecules by targeting corresponding molecules such as EGFR, MEK, PI3K [27,28] (Fig. 1).…”

Section: Oncogenes In Pdac and Potential Targetsmentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

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Section: Oncogenes In Pdac and Potential Targetsmentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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“…Consequently, Akt inhibition shows great therapeutic potential in the treatment of many malignancies. Furthermore, p-Akt expression level has been associated with the prognosis of several cancers [ 14 , 15 ], including NSCLC where p-Akt overexpression has been reported as an indicator of poor prognosis [ [16] , [17] ].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylated-Akt overexpression is associated with a higher risk of brain metastasis in patients with non-small cell lung cancer

Jin

Yuan

et al. 2019

Biochemistry and Biophysics Reports

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Brain metastasis (BM) of non-small cell lung cancer (NSCLC) is relatively common and has a poor prognosis. Moreover, identifying which patients are more likely to develop BM is challenging. Akt, a serine/threonine-specific protein kinase, can be activated in various tumors, including lung cancer, and may be associated with poor prognosis. Here, we used immunohistochemistry to evaluate phosphorylated-Akt (p-Akt) expression in tumor tissues of 99 NSCLC patients. We also analyzed the genotype of the patients for two single nucleotide polymorphisms (SNPs) of the AKT1 gene, rs2498804 and rs2494732. We found that p-Akt expression differs between NSCLC patients and correlates with the risk of BM. Indeed, patients exhibiting medium to high p-Akt expression had a higher incidence of BM than those exhibiting low to no p-Akt expression (39% vs 16%). Our data also show that patients with the rs2498804 GT/GG and rs2494732 CT/TT variant genotypes were more likely to exhibit higher levels of p-Akt expression than those with the rs2498804 TT and rs2494732 CC variant genotypes (35% vs. 24% and 37% vs. 25%, respectively). Our results suggest that the level of expression of p-Akt, which may be affected by the AKT1 genotype, is correlated with the risk of BM. However, further studies are needed to establish p-Akt as a predictive marker for BM in NSCLC patients.

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“…Furthermore,PPI analyses indicated that INPP5B and PTEN might interact. PTEN is known to be a tumor suppressor by inhibiting the activation of PI3/Akt pathway [44]. Although our experimental results indicated that overexpression of INPP5B had no effect on PTEN expression(Additional le 1: Fig.…”

Section: Discussionmentioning

confidence: 82%

Decreased INPP5B Expression Predicts Poor Prognosis in Lung Adenocarcinoma

Deng

et al. 2021

Preprint

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Background Inositol Polyphosphate-5-Phosphatase B (INPP5B), ainositol 5-phosphatase, plays important roles in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential value of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD. Methods TCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic value of INPP5B was determined by Kaplan-Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses.The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein-protein interaction(PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays. Result INPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And low expression of INPP5B was associated with adverse-pathology features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for patients with LUAD. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the acitivity of PI3K/Akt signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the Akt pathway. Conclusion Our results demonstrated that INPP5Bcould inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for patients with LUAD. Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People’s Hospital. The Ethics Committee of Hangzhou First People's Hospital have approved this study. (registration number:ⅡT-20210907-0031-01；registration date:2021.09.13)

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PI3 Kinase Pathway Mutations in Human Cancers

Cited by 9 publications

References 70 publications

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Phosphorylated-Akt overexpression is associated with a higher risk of brain metastasis in patients with non-small cell lung cancer

Decreased INPP5B Expression Predicts Poor Prognosis in Lung Adenocarcinoma

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