Analyse des mutations des gènes RAS par technique Cobas ® au sein d’une structure de pathologie libérale : étude médico-économique et moléculaire comparative avec une plateforme labellisée INCa

Albertini, A.v.; Raoux, Delphine; Neumann, Frédéric; Rossat, Stéphane; Tabet, Fouzi; Pédeutour, Florence; Duranton-Tanneur, Valérie; Kubiniek, Valérie; Vire, O; Weinbreck, Nicolas

doi:10.1016/j.bulcan.2017.05.005

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…KRAS and PIK3CA are essential editing targets in KRAS-mutated CRC due to their high mutation frequencies. 5,39 MEK and MTOR were chosen for further depletion because of the crosstalk between the MAPK and PI3K pathways. 40 Many studies have demonstrated the potent suppression effect of dual inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

et al. 2021

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Mutated KRAS promotes the activation of the MAPK pathway and the progression of colorectal cancer (CRC) cells. Aberrant activation of the PI3K pathway strongly attenuates the efficacy of MAPK suppression in KRAS‐mutated CRC. The development of a novel strategy targeting a dual pathway is therefore highly essential for the therapy of KRAS‐mutated CRC. In this study, a quadruple‐depleting system for the KRAS, MEK1, PIK3CA, and MTOR genes based on CRISPR/SaCas9 was developed. Adenovirus serotype 5 (ADV5) was integrated with two engineered proteins, an adaptor and a protector, to form ADV‐protein complex (APC) for systemic delivery of the CRISPR system. Quadruple‐editing could significantly inhibit the MAPK and PI3K pathways in CRC cells with oncogenic mutations of KRAS and PIK3CA or with KRAS mutation and compensated PI3K activation. Compared with MEK and PI3K/MTOR inhibitors, quadruple‐editing induced more significant survival inhibition on primary CRC cells with oncogenic mutations of KRAS and PIK3CA. The adaptor specifically targeting EpCAM and the hexon‐shielding protector could dramatically enhance ADV5 infection efficiency to CRC cells and significantly reduce off‐targeting tropisms to many organs except the colon. Moreover, quadruple‐editing intravenously delivered by APC significantly blocked the dual pathway and tumor growth of KRAS‐mutated CRC cells, without influencing normal tissues in cell‐ and patient‐derived xenograft models. Therefore, APC‐delivered quadruple‐editing of the MAPK and PI3K pathways shows a promising therapeutic potential for KRAS‐mutated CRC.

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Section: Discussionmentioning

confidence: 99%

“…KRAS, MEK, PIK3CA, and MTOR are the most common therapeutic targets for CRC treatment at present. KRAS and PIK3CA are essential editing targets in KRAS‐mutated CRC due to their high mutation frequencies 5,39 . MEK and MTOR were chosen for further depletion because of the crosstalk between the MAPK and PI3K pathways 40 .…”

Section: Discussionmentioning

confidence: 99%

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

et al. 2021

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“…The protagonist of this paper, Trametinib, is a selective inhibitor of MEK1/2, which can downregulate the phosphorylation level of downstream proteins such as ERK (Extracellular Signal-Regulated Kinase) by inhibiting MEK expression 7 . This drug is currently approved for use in combination with Dabrafenib for unresectable or metastatic melanoma, metastatic BRAFV600E mutation-positive non-small-cell lung cancers, and metastatic BRAFV600E mutation-positive anaplastic thyroid cancer.…”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma

Cheng,

Zhou,

Chen

et al. 2024

Sci Rep

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Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to most chemotherapy drugs, leading to poor chemotherapy efficacy. Recently, Trametinib and Palbociclib have promising prospects in the treatment of pancreatic cancer. This article aims to explore the effects of Trametinib on pancreatic cancer and address the underlying mechanism of resistance as well as its reversal strategies. The GDSC (Genomics of Drug Sensitivity in Cancer) and CTD2 (Cancer Target Discovery and Development) were utilized to screen the potential drug candidate in PDAC cell lines. The dose-increase method combined with the high-dose shock method was applied to induce the Trametinib-resistant PANC-1 and MIA PaCa-2 cell lines. The CCK8 proliferation assay, colony formation assay, flow cytometry, and western blot were conducted to verify the inhibitory effect of Trametinib and Palbociclib. RNA-seq was performed in resistant PDAC cell lines to find the differential expression genes related to drug resistance and predict pathways leading to the reversal of Trametinib resistance. The GDSC and CTD2 database screening revealed that Trametinib demonstrates a significant inhibitory effect on PDAC. We found that Trametinib has a lower IC50 than Gemcitabine in PDAC cell lines. Both Trametinib and Gemcitabine can decrease the proliferation capacity of pancreatic cells, induce cell cycle arrest, and increase apoptosis. Simultaneously, the phosphorylation of the AKT and ERK pathways were inhibited by the treatment of Trametinib. In addition, the RNA-seq of Trametinib-induced resistance PDAC cell lines reveals that the cyclin-dependent kinase (CDK)-RB-E2F regulatory axis and G2/M DNA damage checkpoint might lead the drug resistance. Besides, the combination of Trametinib with Palbociclib could inhibit the proliferation and cell cycle of both resistant cells lines and also restore the sensitivity of drug-resistant cells to Trametinib. Last but not least, the interferon-α and interferon-γ expression were upregulated in resistance cell lines, which might lead to the reversal of drug resistance. The study shows Trametinib has a critical inhibitory effect on PDAC. Besides, the combination of Trametinib with Palbociclib can inhibit the proliferation of PDAC-resistant cells.

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“…There are some targeted therapies, such as trastuzumab for HER-2, bevacizumab for VEGF-A ( Wadhwa et al, 2013 ), and cetuximab for EGFR, that are currently widely used. However, only 5%–10% of GC patients are HER-2 positive, half of the GC patients have mutant KRAS genes ( Albertini et al, 2017 ) and not all patients respond well to bevacizumab. All these indicate that more genes that can better reflect the severity and evaluate the prognosis of GC need to be identified ( Wu et al, 2014 ; Ciliberto et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis of matrix metalloproteinases affecting the prognosis and immunogenic profile of gastric cancer

Yuan

Xiao

et al. 2023

Front. Genet.

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This study systematically and comprehensively analyzed the characteristics of matrix metalloproteinases (MMPs) in gastric cancer (GC) and revealed the relationship between MMPs and prognoses, clinicopathological features, tumor microenvironment, gene mutations, and drug therapy response in patients with GC. Based on the mRNA expression profiles of 45 MMP-related genes in GC, we established a model that classified GC patients into three groups based on cluster analysis of the mRNA expression profiles. The 3 groups of GC patients showed significantly different prognoses as well as tumor microenvironmental characteristics. Next, we used Boruta’s algorithm and PCA method to establish an MMP scoring system and found that lower MMP scores were associated with better prognoses, lower clinical stages, better immune cell infiltration, lower degrees of immune dysfunction and rejection, and more genetic mutations. Whereas a high MMP score was the opposite. These observations were further validated with data from other datasets, showing the robustness of our MMP scoring system. Overall, MMP could be involved in the tumor microenvironment (TME), clinical features, and prognosis of GC. An in-depth study of MMP patterns can better understand the indispensable role of MMP in the development of GC and reasonably assess the survival prognosis, clinicopathological features, and drug efficacy of different patients, thus providing clinicians with a broader vision of GC progression and treatment.

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Analyse des mutations des gènes RAS par technique Cobas ® au sein d’une structure de pathologie libérale : étude médico-économique et moléculaire comparative avec une plateforme labellisée INCa

Cited by 6 publications

References 14 publications

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

Quadruple‐editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS‐mutated colorectal cancer cells

CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma

Genomic analysis of matrix metalloproteinases affecting the prognosis and immunogenic profile of gastric cancer

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