Gastric cancer management: Kinases as a target therapy

Farran, Batoul; Müller, Susanne; Montenegro, Raquel Carvalho

doi:10.1111/1440-1681.12743

Cited by 31 publications

(24 citation statements)

References 90 publications

(161 reference statements)

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“…The PI3K/AKT pathway is an important therapeutic target because its components, including PIK3CA, are frequently activated in cancer cells; indeed, several PI3K pathway inhibitors are currently in clinical trials [ 26 , 27 ]. Therefore, identifying patients who might benefit from targeted therapy is of great importance [ 28 , 29 ]. An increasing number of studies are focused on PIK3CA dysregulation and its potential impact in GC, one example being the MAGIC trial [ 30 ], highlighting the urgent need to elucidate more precisely the contribution of PIK3CA alterations to GC.…”

Section: Discussionmentioning

confidence: 99%

Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis

Chen

et al. 2018

Oncotarget

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BackgroundIncreasing evidence suggests that dysregulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) plays an important role in carcinogenesis. However, the relationship between PIK3CA expression and gastric cancer (GC) prognosis remains controversial.MethodsWe searchedPubMed, Embase, Web of Science, and the Cochrane Library databases for relevant studies up to June 30, 2017. Primary outcomes were hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CI) for association with overall survival and clinicopathological features.ResultsEleven studies comprising 2481 GC patients were analyzed. Pooled analysis showed that PIK3CA upregulation was significantly associated with worse overall survival (HR = 1.79, 95% CI 1.42–2.27, p< 0.001) at the protein (HR = 1.94, 95% CI 1.52–2.47, p< 0.001) but not the gene (HR = 1.57, 95% CI 0.92–2.69, p= 0.097) level. PIK3CA gene mutation did not correlate with overall survival (HR = 1.05, 95% CI 0.83–1.34, p= 0.666) but was significantly associated with poor tumor differentiation (OR = 0.37, 95% CI 0.17–0.76, p= 0.011).ConclusionHigh PIK3CA protein expression predicted poor prognosis in GC, whereas PIK3CA gene amplification or mutation did not. Moreover, PIK3CA mutation was an indicator of poorly differentiated tumors.

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Section: Discussionmentioning

confidence: 99%

Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis

Chen

et al. 2018

Oncotarget

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“…The PTEN/PI3K/AKT axis is a crucial signaling pathway in various of tumor biological processes, [24][25][26][27] and molecules targeting PI3K pathway is widely used in GC therapies. 28,29 PIK3CA and PTEN mutations are common events in genetic mutations in cancer progression. [30][31][32] Previous study indicates that PIK3CA mutations are closely associated with survival time of patients with glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

<p>The Down-Regulation of lncRNA PCAT18 Promotes the Progression of Gastric Cancer via MiR-107/PTEN/PI3K/AKT Signaling Pathway</p>

Chen

Zhao

Wang

et al. 2019

OTT

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Purpose: LncRNAs are important regulators in cancers. In this study, we investigated the role of lncRNA PCAT18 in gastric cancer (GC). Patients and Methods: The level of PCAT18 in GC tissues and cells was determined by qRT-PCR. The cellular behaviors of GC cells with knockdown or overexpression of PCAT18 were respectively detected by CCK-8 assays, colony formation assays, flow cytometry and Western blot. A GC mice model was established by subcutaneous injection of MGC-803 and HGC-27 cells with the knockdown or overexpression of PCAT18. The tumor size and weight were measured, and IHC was performed to determine ki-67 level. Predicted by bioinformatics software and confirmed by dual-luciferase reporter assay, PCAT18 was involved in miR-107/PTEN axis, thus, the expression of and relationship among PCAT18, miR-107 and PTEN pathway were explored in clinical cases and GC cell lines. Rescue assay was performed in GC cells by co-transfection with miR-107 mimic or PCAT18. The PTEN/ PI3K/AKT pathway was then detected by Western blot. Results: PCAT18 was down-regulated in GC tissues and cells, and it had a significant diagnostic value for GC. The expression of PCAT18 was highly associated with tumor size, and PCAT18 was found to inhibit GC growth in vitro and in vivo. It was also found that PCAT18 was involved in PTEN/PI3K/AKT signaling pathway through targeting miR-107. Conclusion: PCAT18 inhibits the progression of GC via miR-107/PTEN/PI3K/AKT signaling pathway. Additionally, PCAT18 is possibly a promising target for treatment of GC.

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“…The efficacy of kinase inhibitors for many different types of cancers has prompted the investigation of these compounds also in GC [6,21,22]. However, so far most clinical trials (clinicaltrial.org NCT00215995, NCT00595985, NCT00725712) with for instance the dual MET/VEGFR2 inhibitor GSK1363089, the multi-target kinase inhibitor sunitinib and the Epidermal Growth Factor Receptor EGFR1 and EGFR2 inhibitor lapatinib, respectively, failed to show beneficial effects [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib

et al. 2020

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Gastric cancer (GC) remains the third leading cause of cancer-related death despite several improvements in targeted therapy. There is therefore an urgent need to investigate new treatment strategies, including the identification of novel biomarkers for patient stratification. In this study, we evaluated the effect of FDA-approved kinase inhibitors on GC. Through a combination of cell growth, migration and invasion assays, we identified dasatinib as an efficient inhibitor of GC proliferation. Mass-spectrometry-based selectivity profiling and subsequent knockdown experiments identified members of the SRC family of kinases including SRC, FRK, LYN and YES, as well as other kinases such as DDR1, ABL2, SIK2, RIPK2, EPHA2, and EPHB2 as dasatinib targets. The expression levels of the identified kinases were investigated on RNA and protein level in 200 classified tumor samples from patients, who had undergone gastrectomy, but had received no treatment. Levels of FRK, DDR1 and SRC expression on both mRNA and protein level were significantly higher in metastatic patient samples regardless of the tumor stage, while expression levels of SIK2 correlated with tumor size. Collectively, our data suggest dasatinib for treatment of GC based on its unique property, inhibiting a small number of key kinases (SRC, FRK, DDR1 and SIK2), highly expressed in GC patients.

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Gastric cancer management: Kinases as a target therapy

Cited by 31 publications

References 90 publications

Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis

Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis

<p>The Down-Regulation of lncRNA PCAT18 Promotes the Progression of Gastric Cancer via MiR-107/PTEN/PI3K/AKT Signaling Pathway</p>

Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib

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