Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence

Oncogene
Wen-Bin OuJonathan A Fletcher

Abstract

Oncogenic KIT or PDGFRA tyrosine kinase mutations are compelling therapeutic targets in most gastrointestinal stromal tumors (GISTs), and the KIT inhibitor, imatinib, is therefore standard of care for patients with metastatic GIST. However, some GISTs lose expression of KIT oncoproteins, and therefore become KIT-independent and are consequently resistant to KIT-inhibitor drugs. We identified distinctive biologic features in KIT-independent, imatinib-resistant GISTs as a step towards identifying drug targets in these poorly understood tumors. We developed isogenic GIST lines in which the parental forms were KIT oncoprotein-dependent, whereas sublines had loss of KIT oncoprotein expression, accompanied by markedly downregulated expression of the GIST biomarker, protein kinase C-theta (PRKCQ). Biologic mechanisms unique to KIT-independent GISTs were identified by transcriptome sequencing, qRT-PCR, immunoblotting, protein interaction studies, knockdown and expression assays, and dual-luciferase assays. Transcriptome sequencing showed that cyclin D1 expression was extremely low in two of three parental KIT-dependent GIST lines, whereas cyclin D1 expression was high in each of the KIT-independent GIST sublines. Cyclin D1 inhibition i...Continue Reading

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Citations

Nov 30, 2019·British Journal of Cancer·Mengyuan HuangWen-Bin Ou
Oct 9, 2020·Signal Transduction and Targeted Therapy·Xiaoling SongYingbin Liu
Jan 10, 2021·International Journal of Molecular Sciences·Christos VallilasMichalis V Karamouzis
Feb 11, 2021·Biomolecules·Amandine NicolleKarine Belguise

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Methods Mentioned

BETA
biopsies
Assay
transfection
transfections
immunoprecipitation
immunoprecipitations
GIST
PCR
RNA-seq
protein assay

Software Mentioned

Ensembl Browser
Spot
Modfit LT
Spot RT

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