STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications

Tuveson, David A.; Willis, Nicholas A.; Jacks, Tyler; Griffin, James D.; Singer, Samuel; Fletcher, Christopher D.�M.; Fletcher, Jonathan A.; Demetri, George D.

doi:10.1038/sj.onc.1204704

Cited by 614 publications

(400 citation statements)

References 25 publications

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“…The GIST882 tumor cell line possessing a homozygous mutation in KIT exon 13, the GIST-T1/829 subline derived from parental GIST-T1 cells possessing a secondary A829P kinase domain mutation, and the GIST430 tumor cell line possessing a primary KIT exon 11 deletion with a secondary mutation (V654A substitution), were all generously provided by Jonathan A. Fletcher (20). Cells were grown as described in (11) (GIST-T1), (21) (GIST882) and (20) (GIST-T1/829 and GIST430) and were routinely (last tested April 2016) monitored by Sanger sequencing to confirm their KIT mutation status and cell line identity. Imatinib mesylate (IM) (Gleevec™) was obtained from the Fox Chase Cancer Center (FCCC) Pharmacy, dissolved in sterile PBS and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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Section: Methodsmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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“…22 Exons 9,11,13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRa gene were amplified by PCR. The primer sequences for PCR are summarized in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…2,5,6 C-kit has been implicated in the tumorigenesis of a variety of neoplasms including gastrointestinal stromal tumors (GISTs), small cell lung carcinomas, melanoma, and breast carcinoma. [7][8][9] Imatinib mesylate (Glivec internationally, Gleevec in the United States) 10,11 is a tyrosine kinase inhibitor and is used to treat GISTs that express ckit. 12 In 5-10% of GISTs that are c-kit mutation negative, mutations in another gene, platelet-derived growth receptor-a (PDGFRa; exons 12, 14, and 18), have been identified.…”

mentioning

confidence: 99%

Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon

Djordjevic

Hanna

2008

Modern Pathology

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The expression of c-kit, a protooncogene tyrosine kinase receptor (CD117), in phyllodes tumors of the breast has been the subject of recent investigations. We examined stromal c-kit expression by immunohistochemistry in 68 cases comprising fibroadenomas, fibroadenomas with cellular stroma, and benign, borderline, and malignant phyllodes tumors. Membrane staining was identified in the epithelium of 82% of cases, representing all diagnostic categories in the study. Membrane and cytoplasmic staining was detected in scant cells in the stroma in 74% of the cases in the study, again, across all diagnostic entities. However, when toluidine blue and tryptase staining was performed, the staining pattern matched that of c-kit in the number of cells and their distribution, thereby confirming the presence of mast cells and excluding any appreciable level of true stromal c-kit staining. One borderline and one malignant phyllodes tumor showed a diffuse weak stromal signal, which could not be accounted for by toluidine blue and tryptase. These cases were further tested for the presence of known activating mutations of c-kit and PDGFR-a, and yielded negative results. Our findings indicate that c-kit is an unlikely player in the pathogenesis of fibroepithelial lesions of the breast. The positive stromal staining suggested previously by other authors may be attributed to mast cells. C-kit, therefore, has neither a diagnostic nor a prognostic role in phyllodes tumors, and there is no rationale for the treatment of recurrent of malignant phyllodes tumor patients with tyrosine kinase inhibitors.

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“…However, radiation and chemotherapy provide a o10% response rate (Dematteo et al, 2000(Dematteo et al, , 2002. Imatinib mesylate (IM), an orally administered selective c-Kit/PDGFR tyrosine kinase inhibitor, abrogates cellular proliferation of GIST cells in culture (Tuveson et al, 2001) and inhibits the constitutively active phosphorylating activity of c-Kit and PDGFR by binding the adenosine 5 0 -trisphosphate (ATP) site preventing the activation of PI-3K and mitogenactivated protein kinase dependent pathways (Heinrich et al, 2003). A randomized trial of GIST patients treated with IM showed that 5% patients achieved a complete response, 47% partial response and 32% stable disease (Verweij et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications

Cited by 614 publications

References 25 publications

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

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