Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

Gleixner, Karoline V.; Mayerhofer, Matthias; Sonneck, Karoline; Gruze, Alexander; Samorapoompichit, Puchit; Baumgartner, Christian; Lee, Francis Y.; Aichberger, Karl J.; Manley, Paul W.; Fabbro, Doriano; Pickl, Winfried F.; Sillaber, Christian; Valent, Peter

doi:10.3324/haematol.11339

Cited by 88 publications

(90 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…During the past few years, several promising new drugs, potentially useful as cytoreductive agents in ASM and MCL, have been developed and tested in preclinical studies. One of these agents is the multi-kinase blocker midostaurin (20)(21)(22)(23)(24). However, although mediator-related symptoms often improve, hematologic responses are usually short-lived (20,24,30).…”

Section: Discussionmentioning

confidence: 99%

“…Flow cytometry analyses were performed on primary blood basophils and HMC-1.2 cells according to published methods (23,32,46). A detailed description is provided in Supplementary Material and Methods.…”

Section: Flow Cytrometry Analysesmentioning

confidence: 99%

“…A novel promising strategy is to use KIT-targeting tyrosine kinase inhibitors (TKI) (19)(20)(21)(22)(23)(24)(25). However, the KIT D816V mutant is resistant against several of these TKI, including imatinib (21,25,26).…”

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%

See 3 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Flow Cytrometry Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Furthermore, dasatinib may synergize with PKC412 and chemotherapy in this regard [114][115][116]. In the largest study of dasatinib therapy in SM [117], the drug was given at a starting dose of 70 mg PO bid to 33 SM patients:18 ISM, 9 ASM, and 6 with SM-AHNMD.…”

Section: Investigational Agentsmentioning

confidence: 99%

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

Pardanani

2015

American J Hematol

View full text Add to dashboard Cite

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.

show abstract

Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management

Pardanani

2011

American J Hematol

View full text Add to dashboard Cite

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 prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), 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. Risk‐adapted therapy: 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. Dasatinib's in vitro anti‐ KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients. Am. J. Hematol. 86:363–371, 2011. © 2011 Wiley‐Liss, Inc.

show abstract

Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

Cited by 88 publications

References 46 publications

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

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

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

Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management

Contact Info

Product

Resources

About