Resistance to imatinib, low-grade FDG-avidity on PET, and acquired KIT exon 17 mutation in gastrointestinal stromal tumour

Grimpen, Florian; Yip, Desmond; McArthur, Grant A.; Waring, Paul; Goldstein, David; Loughrey, Maurice B.; Beshay, Victoria; Chong, Guan C.

doi:10.1016/s1470-2045(05)70321-1

Cited by 34 publications

(15 citation statements)

References 14 publications

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“…Nishida et al [13] reported that 80% of patients with imatinib-resistant GIST had secondary mutations, and that additional cis-positioned mutations in the kinase domains were a major cause of secondary resistance to imatinib. Similar results have been reported in several small case series [14][15][16][17][18][19][20][21][22][23].…”

Section: Molecular Mechanism Of Imatinib Resistancesupporting

confidence: 91%

Current clinical strategy for imatinib-resistant gastrointestinal stromal tumors

Yamamoto

Konno

2009

Clin J Gastroenterol

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Before the advent of imatinib, no effective agent was available for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GISTs). However, the treatment strategy changed and the prognosis of patients with advanced or recurrent GIST improved remarkably after the development of imatinib. Despite the high rate of clinical benefit of imatinib in GIST patients, more than half of GIST patients eventually develop primary or secondary resistance to imatinib, resulting in the progression of the disease. It has also been reported that about 5% of patients are intolerant to imatinib. An effective treatment strategy for imatinib-resistant GIST is needed. The National Comprehensive Cancer Network guidelines recommend a multidisciplinary approach, but the therapeutic modalities are still limited, and none are able to achieve complete remission. In this review, we summarize the current understandings of the mechanism of imatinib resistance and the clinical strategies used against imatinib-resistant GIST, including surgical intervention, escalation of imatinib dose, and use of sunitinib or other agents. Understanding these issues may help in the development of a new treatment paradigm for GIST patients.

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Section: Molecular Mechanism Of Imatinib Resistancesupporting

confidence: 91%

Current clinical strategy for imatinib-resistant gastrointestinal stromal tumors

Yamamoto

Konno

2009

Clin J Gastroenterol

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“…In future clinical studies, we will test whether the metabolic effect [increased glucose uptake with elevated (glycolysis/ TCA) ratios] can be detected in the "to-be-resistant" cells prior to an increase in the white cell count. Indeed, increased accumulation of FDG in positron emission tomography studies (indicating increased GLUT-1 and hexokinase activity) often appears before anatomically visible tumor growth in therapyresistant solid tumors (42). If validated, the glucose assessment can help to (a) develop a clinical MRS-based metabolic profile in peripheral blood (equivalent to positron emission tomography studies in solid tumors) for the early detection of imatinib resistance in patients with CML, and (b) to evaluate the metabolic mechanisms of action for novel small molecule tyrosine kinase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL–Positive Cells

Kominsky

Klawitter

Brown

et al. 2009

Clinical Cancer Research

100

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The development of imatinib resistance has become a significant therapeutic problem in which the etiology seems to be multifactorial and poorly understood. As of today, clinical criteria to predict the development of imatinib resistance in chronic myelogenous leukemia (CML), other than rebound of the myeloproliferation, are under development. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib because imatinib-resistant gastrointestinal stromal KIT-positive tumors reveal highly elevated glucose uptake in radiologic images. We used nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry to assess 13 C glucose uptake and metabolism (glycolysis, TCA cycle, and nucleic acid ribose synthesis) during imatinib treatment in CML cell lines with different sensitivities to imatinib. Our results show that sensitive K562-s and LAMA84-s BCR-ABL-positive cells have decreased glucose uptake, decreased lactate production, and an improved oxidative TCA cycle following imatinib treatment. The resistant K562-r and LAMA84-r cells maintained a highly glycolytic metabolic phenotype with elevated glucose uptake and lactate production. In addition, oxidative synthesis of RNA ribose from 13 C-glucose via glucose-6-phosphate dehydrogenase was decreased, and RNA synthesis via the nonoxidative transketolase pathway was increased in imatinib-resistant cells. CML cells which exhibited a (oxidative/nonoxidative) flux ratio for nucleic acid ribose synthesis of >1 were sensitive to imatinib. The resistant K562-r and LAMA84-r exhibited a (oxidative/nonoxidative) flux ratio of <0.7. The changes in glucose uptake and metabolism were accompanied by intracellular translocation of GLUT-1 from the plasma membrane into the intracellular fraction in sensitive cells treated with imatinib, whereas GLUT-1 remained located at the plasma membrane in LAMA84-r and K562-r cells. The total protein load of GLUT-1 was unchanged among treated sensitive and resistant cell lines. In summary, elevated glucose uptake and nonoxidative glycolytic metabolic phenotype can be used as sensitive markers for early detection of imatinib resistance in BCR-ABL-positive cells.Chronic myelogenous leukemia (CML) is a myeloproliferative disorder associated with a t(9;22) chromosomal translocation which gives rise to the Philadelphia chromosome, resulting in the production of a BCR-ABL fusion protein (1, 2). A large portion of a proto-oncogene on chromosome 9, called ABL, is translocated to the BCR gene on chromosome 22 (2). The two gene segments are fused and ultimately produce a chimeric protein that is larger than the normal ABL protein (3).The development of novel targeted cancer-specific therapies is a major strategy in oncology, and the treatment of CML with imatinib mesylate (Gleevec or Glivec, formerly known as STI571) was the first successful proof of concept. Imatinib mesylate has revolutionized the way we treat CML its high level of activity, low toxicity...

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“…It is now established that acquired mutations in KIT or PDGFRA account for most secondary resistance, and that these mutations occur almost exclusively in the same gene and allele as the primary oncogenic driver mutation. 35,[134][135][136][137][138][139][140] In a phase II imatinib study for advanced GIST, 67% of the patients whose tumor showed imatinib resistance had a new, or secondary, mutation in KIT. Notably, these mutations were common among tumors with a primary exon 11 mutation, but were not observed in wild-type GIST samples.…”

Section: Secondary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Resistance to imatinib, low-grade FDG-avidity on PET, and acquired KIT exon 17 mutation in gastrointestinal stromal tumour

Cited by 34 publications

References 14 publications

Current clinical strategy for imatinib-resistant gastrointestinal stromal tumors

Current clinical strategy for imatinib-resistant gastrointestinal stromal tumors

Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL–Positive Cells

Gastrointestinal stromal tumors: what do we know now?

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