Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412

Growney, Joseph D.; Clark, Jennifer J.; Adelsperger, Jennifer; Stone, Richard; Fabbro, Doriano; Griffin, James D.; Gilliland, D. Gary

doi:10.1182/blood-2004-12-4617

Cited by 227 publications

(176 citation statements)

References 23 publications

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“…Similar discrepancies were found in paper describing studies on Ba/F3-c-Kit-D816V cells with some investigators using medium with [5,6] and some investigators using medium without IL-3 [7,8] for long-term culture. Since there are differences in the signaling pathways induced by IL-3 as compared to the oncogenic mutants of Flt3 and c-Kit that might influence gene expression and ultimately cell behavior, we decided to investigate whether different culture conditions could influence the signal transduction outcome and biological responses of Flt3-ITD and c-Kit-D816V, respectively, in Ba/F3 cells.…”

supporting

confidence: 79%

The presence or absence of IL-3 during long-term culture of Flt3-ITD and c-Kit-D816V expressing Ba/F3 cells influences signaling outcome

Kazi¹,

Sun²,

Rönnstrand³

2013

Experimental Hematology

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supporting

confidence: 79%

The presence or absence of IL-3 during long-term culture of Flt3-ITD and c-Kit-D816V expressing Ba/F3 cells influences signaling outcome

Kazi¹,

Sun²,

Rönnstrand³

2013

Experimental Hematology

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“…2) Midostaurin (PKC412) has in vitro activity against kinase domain KIT mutants (D816Y and D816V) [99,119], and treatment of a patient with MCL who harbored KITD816V resulted in transient clinical benefit [120]. In the global Phase 2 CPKC412D2201 trial, 116 patients with advanced SM were enrolled; the efficacy population comprised of 89 patients (73 with ASM, of which 57 had an associated hematological malignancy, and 16 with MCL); patients were treated with PKC412 at 100 mg BID [121].…”

Section: Investigational Agentsmentioning

confidence: 99%

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Pardanani

2015

American J Hematol

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Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/−corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.

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“…However, the KIT D816V mutant is resistant against several of these TKI, including imatinib (21,25,26). PKC412 (midostaurin) is a multi-kinase inhibitor directed against wild type (wt) KIT and several KIT mutants, including D816V (21,27,28). Additional oncogenic kinases are also recognized by midostaurin (27,29).…”

Section: Introductionmentioning

confidence: 99%

“…However, the exact profile of molecular targets of midostaurin expressed by neoplastic MC remains unknown. A number of in vitro studies have shown that midostaurin inhibits the proliferation and survival of neoplastic MC exhibiting KIT D816V (21,23,28). In addition, midostaurin can suppress growth of neoplastic MC in vivo in patients with advanced SM (20,24).…”

Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412

Cited by 227 publications

References 23 publications

The presence or absence of IL-3 during long-term culture of Flt3-ITD and c-Kit-D816V expressing Ba/F3 cells influences signaling outcome

The presence or absence of IL-3 during long-term culture of Flt3-ITD and c-Kit-D816V expressing Ba/F3 cells influences signaling outcome

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

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