Genetic progression in gastrointestinal stromal tumors: mechanisms and molecular interventions

Li, Ké; Cheng, Haibo; Li, Zhang; Pang, Yu; Xing, Jia; Xie, Feifei; Hu, Guohong; Cai, Qing-Qing; Wang, Yuexiang

doi:10.18632/oncotarget.16014

Cited by 20 publications

(14 citation statements)

References 96 publications

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“…As our review focuses on solid tumours we only discuss imatinib in GIST. The development of GIST is associated with several gain‐of‐function mutations in c‐KIT and PDGFR …”

Section: Methodsmentioning

confidence: 99%

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Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

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Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

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“…As our review focuses on solid tumours we only discuss imatinib in GIST. The development of GIST is associated with several gain‐of‐function mutations in c‐KIT and PDGFR …”

Section: Methodsmentioning

confidence: 99%

“…The development of GIST is associated with several gain-of-function mutations in c-KIT and PDGFR. 33…”

Section: Imatinibmentioning

confidence: 99%

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

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“…Mutations in the PDGFRA gene are identified in exons 12, 14, 18 to 5–10% of patients. Approximately 10–15% of patients have no mutations and are classified as wild type GIST [ 6 , 7 ]. Molecular characterization of GISTs has revealed novel mutations to BRAF, neurofibromatosis type 1 (NF1), and succinate dehydrogenase (SDH) in small percentages [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

Vallilas

Sarantis

Kyriazoglou

et al. 2021

IJMS

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Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

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“…The main initiating events in GIST are gain-of-function mutations in two oncogenes from the RTK family—KIT (70–80%) or platelet-derived growth factor receptor-α (PDGFRA; 10%)—that result in constitutive activation of the receptor and downstream signaling pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) or Janus kinase (JAK)/signal transducer and activator of transcription (STAT) [ 3 , 4 ], whereas the lately discovered ETS variant transcription factor 1 (ETV1) is required for the growth and survival of GIST cells [ 5 ]. Targeting mutant RTKs with RTK inhibitors are effective in patients with advanced tumors; however, a large proportion of the patients acquire resistance to the treatment in the long run [ 6 ], urging the need for the search of new treatment methods and therapeutic targets. Although the main aspects and initial events of GIST biology are already well understood, little is known about the mechanisms underlying the regulation of oncogene expression signatures.…”

Section: Introductionmentioning

confidence: 99%

The Role of miR-375-3p and miR-200b-3p in Gastrointestinal Stromal Tumors

Gyvyte

Lukoševičius

Inčiūraitė

et al. 2020

IJMS

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Deregulated microRNA (miRNA) expression profiles and their contribution to carcinogenesis have been observed in virtually all types of human cancer. However, their role in the pathogenesis of rare mesenchymal gastrointestinal stromal tumors (GISTs) is not well defined, yet. In this study, we aimed to investigate the role of two miRNAs strongly downregulated in GIST—miR-375-3p and miR-200b-3p—in the pathogenesis of GIST. To achieve this, miRNA mimics were transfected into GIST-T1 cells and changes in the potential target gene mRNA and protein expression, as well as alterations in cell viability, migration, apoptotic cell counts and direct miRNA–target interaction, were evaluated. Results revealed that overexpression of miR-375-3p downregulated the expression of KIT mRNA and protein by direct binding to KIT 3′UTR, reduced GIST cell viability and migration rates. MiR-200b-3p lowered expression of ETV1 protein, directly targeted and lowered expression of EGFR mRNA and protein, and negatively affected cell migration rates. To conclude, the present study identified that miR-375-3p and miR-200b-3p have a tumor-suppressive role in GIST.

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Genetic progression in gastrointestinal stromal tumors: mechanisms and molecular interventions

Cited by 20 publications

References 96 publications

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

The Role of miR-375-3p and miR-200b-3p in Gastrointestinal Stromal Tumors

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