AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit

Lin, Tzu‐Yin; Fenger, Joelle M.; Murahari, Sridhar; Bear, Misty D.; Kulp, Samuel K.; Wang, Dasheng; Chen, Ching Shih; Kisseberth, William C.; London, Cheryl A.

doi:10.1182/blood-2009-07-231985

Cited by 73 publications

(71 citation statements)

References 40 publications

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“…20,29,38 Mutations result in constitutive activation of KIT, initiating signaling cascades leading to proliferation, survival, and invasion. 9,[15][16][17][18]21,22,29 One group reported that the presence of ITD mutations of c-KIT or aberrant cytoplasmic KIT protein localization was significantly associated with higher values of Ki67. 37 It is not clear from any study of cutaneous MCT if subcutaneous MCT were included; if so, the data could be compromised.…”

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Canine Subcutaneous Mast Cell Tumors

Thompson

Yager²,

Best³

et al. 2010

Vet Pathol

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Molecular assays are widely used to prognosticate canine cutaneous mast cell tumors (MCT). There is limited information about these prognostic assays used on MCT that arise in the subcutis. The aims of this study were to evaluate the utility of KIT immunohistochemical labeling pattern, c-KIT mutational status (presence of internal tandem duplications in exon 11), and proliferation markers-including mitotic index, Ki67, and argyrophilic nucleolar organizing regions (AgNOR)-as independent prognostic markers for local recurrence and/or metastasis in canine subcutaneous MCT. A case-control design was used to analyze 60 subcutaneous MCT from 60 dogs, consisting of 24 dogs with subsequent local recurrence and 12 dogs with metastasis, as compared to dogs matched by breed, age, and sex with subcutaneous MCT that did not experience these events. Mitotic index, Ki67, the combination of Ki67 and AgNOR, and KIT cellular localization pattern were significantly associated with local recurrence and metastasis, thereby demonstrating their prognostic value for subcutaneous MCT. No internal tandem duplication mutations were detected in exon 11 of c-KIT in any tumors. Because c-KIT mutations have been demonstrated in only 20 to 30% of cutaneous MCT and primarily in tumors of higher grade, the number of subcutaneous MCT analyzed in this study may be insufficient to draw conclusions on the role c-KIT mutations in these tumors. KeywordsAgNOR, canine, case-control study, c-KIT, Ki67, mast cell tumor, mitotic index, prognostic markers Subcutaneous mast cell tumors (MCT) are located in the subcutis, usually surrounded by fat. Until recently, 24,35 this type was not investigated separately from its cutaneous counterpart. Subcutaneous MCT are classified by many as grade II MCT, based on current grading schemes.10,27 Because intermediate (grade II) tumors have a highly variable prognosis 10,25,26 and low interobserver agreement among pathologists, 25,26 accurate prognostic data for the subcutaneous variant of MCT are needed. In a recent retrospective survival analysis of subcutaneous MCT from 306 dogs, 35 we demonstrated that the majority of subcutaneous MCT do not behave aggressively, thus confirming the conclusion of a prior smaller study of subcutaneous MCT.24 Furthermore, our results showed that a strong predictor of survival time, time to local recurrence, and metastasis was mitotic index (MI), assessed as the number of mitotic figures per 10 high-power fields. 35MI is a valuable prognostic test 7,31 and an integral part of grading schemes for cutaneous MCT. 3,10,27 Despite this, there are drawbacks to using MI as a sole determinant for assessment of cellular proliferation. Accurate counting of mitotic figures may be influenced by field selection, plane of section, field diameter, intensity of cytoplasmic granularity (or presence of crush artifact), necrosis, and/or apoptotic cells. All of these variables can contribute to interobserver disagreement. In addition, MI detects only cells in the mitotic phase rather than the enti...

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“…6,9,11,[14][15][16][17][18][19][20][21][22]29,[36][37][38] Studies show that up to 30% of dogs with MCT have mutations in the juxtamembrane domain, 6,9,20,22,29,37,38 the majority of which are internal tandem duplications (ITD) in exon 11. The presence of these mutations is associated with higher-grade tumors.…”

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Canine Subcutaneous Mast Cell Tumors

Thompson

Yager²,

Best³

et al. 2010

Vet Pathol

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“…The major mechanism of HDACIs is believed to be through changes in the transcription of several genes involved in proliferation and cell cycle regulation. In particular, AR42 upregulates expression of p21 (40,41). This protein is known to bind to CDK/cyclin complexes and decrease kinase activation, which leads to cell accumulation in the S and G2/M.…”

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Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Kong

Barisone

Sidhu

et al. 2015

Mol Med

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Checkpoint kinase inhibition has been studied as a way of enhancing the effectiveness of DNA-damaging agents. More recently, histone deacetylase inhibitors have shown efficacy in several cancers, including non-Hodgkin lymphoma. To evaluate the effectiveness of this combination for the treatment of lymphoma, we examined the combination of AR42, a histone deacetylase inhibitor, and checkpoint kinase 2 (CHEK2) inhibitor II in vitro and in vivo. The combination resulted in up to 10-fold increase in potency in five Burkitt lymphoma cell lines when compared with either drug alone. Both drugs inhibited tumor progression in xenograft models, but the combination was more effective than either agent alone, resulting in regression of established tumors. No toxicity was observed. These results suggest that the combination of histone deacetylase inhibition and checkpoint kinase inhibition represent an effective and nontoxic treatment option that should be further explored in preclinical and clinical studies. online address: http://www.molmed.org

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“…In addition, most canine cases with MCTs eventually undergo relapses even after achievement of a remission with TKIs treatment. Therefore, the efficacy of several novel agents such as HSP90 inhibitor [17], HDAC inhibitors [13,18] and calcitriol which is the ligand for vitamin D receptor [24] for canine MCT have recently been examined.Our previous study revealed that the c-KIT receptor of VIMC1 cells, a MCT cell line harboring a point mutation in the extracellular domain of KIT, was consistently phosphorylated in ligand-free medium [33]. Another our study subsequently indicated that the concentration of some TKIs required for inhibition of the phosphorylation of c-Kit receptor was higher than that of cell growth in VIMC1 cells [32].…”

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Screening of Therapeutic Targets for Canine Mast Cell Tumors from a Variety of Kinase Molecules

Takeuchi

Fujino

Watanabe

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. Options of systemic treatment for canine MCT have been still limited and most canine cases with MCTs eventually undergo relapses even after achievement of a remission. Thus additional therapies are required to establish for the tumor. To identify the novel candidate therapeutic targets for canine MCT, the mRNA expression and phosphorylation statuses of several receptor or non-receptor kinases as well as the inhibitory effect of 95 specific inhibitors on the growth were assessed in three canine MCT cell lines (HRMC, VIMC1 and CMMC1). Among the 14 targets, the mRNAs of 11, 7 and 7 kinases were amplified in HRMC, VIMC1 and CMMC1, respectively. The mRNAs of VEGFR3, PDGFR, SRC, YES, LCK and FYN were detected in all cell lines. The phosphorylation of 12, 8 and 7 kinases was observed by using specific antibody arrays in HRMC, VIMC1 and CMMC1, respectively. DTK, EPHB6, AMPK1, CREB, STAT5a and STAT5b were phosphorylated in all cell lines. The 10, 9 and 17 inhibitors exhibited the biological activity against the growth of HRMC, VIMC1 and CMMC1, respectively. Only three inhibitors such as SB218078 (for Chk1), PDGF RTK inhibitor IV (for PDGFR) and radicicol (for Hsp90) suppressed the growth of all three cell lines. The present study indicated that several kinases, such as Chk1, PDGFR and Hsp90, could be used as therapeutic targets in the treatment for canine MCT. Further studies and clinical trials are warranted to apply the inhibitors for the treatment of the tumor.KEY WORDS: canine, cell line, kinases, molecular-targeted therapy, screening method.J. Vet. Med. Sci. 73(10): 1295-1302, 2011 Mast cell tumor (MCT) is one of common skin tumors in dogs and accounts for 7 to 21% of all canine cutaneous tumors [35]. Canine MCTs also arise in extracutaneous sites (visceral MCT) including the conjunctiva, salivary gland, nasopharynx, larynx, oral cavity, gastrointestinal tract, urethra and spine. The clinical behavior of canine MCTs is variable, ranging from slight to severe [7]. Based on the World Health Organization clinical staging and histological grading, treatment for canine MCTs is selected from surgical resection, irradiation, chemotherapy or combination of those [35]. In addition to the conventional therapy, the clinical efficasy of several tyrosine kinase inhibitors (TKIs) such as toceranib, masitinib and imatinib for canine MCT cases has been studied [10,12,22].Several studies revealed that approximately 15 to 40% of canine MCTs contained mutations of KIT gene encoding type III receptor protein tyrosine kinase, c-Kit receptor [15,35]. The several mutations of KIT in canine MCT cases cause constitutive autophosphorylation and activation of cKit receptor without binding of the ligand [15,21,23]. Some studies reported that the TKIs could inhibit c-Kit receptor activation and proliferation of canine MCT cells [9,16,26]. A clinical study reported that canine MCT cases harboring KIT mutation responded to treatment with imatinib [12]. Other studies indicated that canine MCT cases with KIT mutations were more likely t...

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AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit

Cited by 73 publications

References 40 publications

Canine Subcutaneous Mast Cell Tumors

Canine Subcutaneous Mast Cell Tumors

Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Screening of Therapeutic Targets for Canine Mast Cell Tumors from a Variety of Kinase Molecules

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