Activation of Tyrosine Kinases in Cancer

Vlahović, Gordana; Crawford, Jeffrey

doi:10.1634/theoncologist.8-6-531

Cited by 175 publications

(102 citation statements)

References 44 publications

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“…Furthermore, gain-of-function mutations in c-kit have been described primarily in leukemias and gastrointestinal stromal tumors (GIST) (26). Two general mechanisms of c-kit activation in malignant cells have been described: acquisition of activating mutations or autocrine or paracrine stimulation of the receptor by its ligand SCF (27).…”

Section: Introductionmentioning

confidence: 99%

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Bellone¹,

Smirne²,

Carbone³

et al. 2006

Int J Oncol

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Abstract. Autocrine/paracrine stimulation of KIT has been observed in colorectal carcinoma (CRC) cell lines. We investigated the expression of KIT and stem cell factor (SCF) in CRC in comparison with premalignant colon lesions and normal colonic mucosa to assess the prognostic and therapeutic relevance of this receptor/ligand system in CRC. Transcript levels of c-kit and the two SCF splicing variants were determined quantitatively by real-time RT-PCR using cDNA obtained from normal, premalignant and malignant snap frozen colon tissue specimens. Immunohistochemistry with specific anti-KIT and anti-SCF antibodies was performed on paraffin-embedded tissue sections in order to localize the relative protein expression in epithelial compartments. Approximately 10% of patients expressed KIT in their adenoma or primary tumor. The majority of KIT-positive carcinomas co-expressed SCF. Real-time RT-PCR showed expression of c-kit and SCF transcripts in all cDNA specimens examined. A significant association between the co-expression of KIT/SCF and a worse clinical outcome was found. In conclusion, KIT expression was observed in a proportion of premalignant and malignant colonic lesions, while it was virtually absent in normal colon mucosa. Moreover, the majority of KIT-positive carcinomas co-expressed SCF, suggesting the possibility of aberrant signaling by an autocrine loop, as confirmed by the negative prognostic value of this association. Therefore, in the subset of CRC patients with concomitant KIT/SCF expression, the activity of Imatinib mesylate, a selective inhibitor of specific tyrosine kinases including KIT, may be exploited in combination with standard therapy.

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Section: Introductionmentioning

confidence: 99%

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Bellone¹,

Smirne²,

Carbone³

et al. 2006

Int J Oncol

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“…Furthermore, the production of HER2 heterodimers increases the affinity of other members of the family for their respective ligands (Citri, Yarden, 2006). HER3 does not have intrinsic tyrosine kinase activity, and it generates inactive HER3/HER3 dimers, but it can form heterodimers and be phosphorylated by HER2 or HER4 when activated by HER3 ligands (neuregulin 1 and 2) (Yarden, Sliwkowsk, 2001;Vlahovic, Crawford, 2003;Marmor, Skaria, Yarden, 2004). Although it is accepted that HER3 lacks functional residues (including aspartate catalytic action), studies have suggested that it conserves its capacity to phosphorylate its own intracellular domain (Shi et al, 2010).…”

Section: Human Epidermal Receptors: Tyrosine Kinase Structure Ligandmentioning

confidence: 99%

Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

Ferreira

Pessoa

2017

Braz. J. Pharm. Sci.

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“…Tumor tissues were collected in serum-free Hanks' balanced salt solution (HBSS) medium and immediately processed for transplantation. The tumor specimens were cut into small fragments (5 mm 3 ) and kept in a Petri dish containing physiological saline. The tissue fragments were implanted bilaterally into 6-week old NOG mice.…”

Section: Primary Culture and Evaluation Of Tumor Forming Abilitymentioning

confidence: 99%

“…Growth factors, hormones, Matrigel and other supplements were not used. Drug administration was initiated when tumors in each group achieved an average volume of 120-350 mm 3 . Mice were randomly allocated to control and treatment groups.…”

Section: Assessment Of Imatinib Sensitivity Of the Cell Linesmentioning

confidence: 99%

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Establishment and characterization of novel cell lines and xenografts from patients with gastrointestinal stromal tumors

Fukuda¹,

Saikawa²,

Sako³

et al. 2013

Oncology Reports

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Abstract. At present, no suitable GIST model exists for the analysis of drug resistance or metastasis using established human gastrointestinal stromal tumor (GIST) cell lines or xenografts even though the molecular mechanisms of drug resistance, progression and metastasis require clarification. The aim of this study was to establish and characterize human GIST cell lines and xenografts that can be used for evaluating drug resistance or various new molecularly targeted therapies. GIST tissues from patients were cultured and implanted under the skin of NOG (NOD/Shi-scid, IL-2Rrnu) mice. Two new cell lines (GK1C and GK3C) and three xenografts (GK1X, GK2X and GK3X) were generated from these clinical samples. The established GIST cell lines and xenografts were investigated for tumorigenesis and imatinib sensitivity. These cell lines and xenografts showed characteristic GIST morphology and exhibited KIT expression profiles similar to those of the patient samples. In addition, these GIST cell lines and xenografts were sensitive to imatinib. In conclusion, new human GIST cell lines and xenografts were established and maintained through repeated passages. These models will enable further study of combination therapies and the mechanisms of resistance, and allow testing of novel targeted monotherapies and combination therapies. IntroductionHuman gastrointestinal stromal tumors (GISTs), mesenchymal tumors of the gastrointestinal tract (1), originate from the neoplastic transformation of interstitial cells of Cajal (ICC), which frequently express mutations in the c-KIT gene and occasionally in PDGFRA (2). The resulting mutations of KIT and PDGFRA receptors result in constitutive activation of receptor kinase activity leading to downstream effectors that deregulate cell proliferation and survival, thereby accelerating malignant progression (3). Surgery is currently the first-line treatment for patients with primary resectable GISTs (4,5). However, many patients develop recurrent or metastatic disease despite complete surgical resection (6) and since conventional chemotherapy or radiotherapy is usually ineffective (7). Thus, there are no ideal methods for treating such GISTs.Imatinib mesylate (imatinib) is a tyrosine kinase (TK) inhibitor that targets BCR-ABL, PDGFR, KIT, DDR and CSFR, and has been used to treat certain patients with KIT-positive GISTs having constitutive activating mutations in KIT (8). Although more than 80% of inoperable KIT-positive GIST patients exhibit clinical benefits from imatinib, the tumors in most of these patients will eventually progress (9,10). The activity of imatinib differs across various types of c-KIT and PDGFRA mutations, and secondary resistance in imatinibtreated patients often results from an emerging secondary mutation or amplification of c-KIT or PDGFRA (11-13). Approximately 50% of GISTs with secondary resistance to imatinib is caused by mutations in c- . Several studies have reported that the RTK switch is associated with imatinib-resistance, but the other mechanisms of secondary r...

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Activation of Tyrosine Kinases in Cancer

Abstract: ABSTRACT

Cited by 175 publications

References 44 publications

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

Establishment and characterization of novel cell lines and xenografts from patients with gastrointestinal stromal tumors

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