Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation

Gotlib, Jason; Berubé, Caroline; Growney, Joseph D.; Chen, Ching-Cheng; George, Tracy I.; Williams, Christopher S.; Kajiguchi, Tomohiro; Ruan, Jia; Lilleberg, Stan L.; Durocher, Jeffrey A.; Lichy, Jack H.; Wang, Yanfeng; Cohen, Pamela S.; Arber, Daniel A.; Heinrich, Michael C.; Neckers, Len; Galli, Stephen J.; Gilliland, D. Gary; Coutré, Steven

doi:10.1182/blood-2005-04-1568

Cited by 222 publications

(197 citation statements)

References 26 publications

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“…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%

“…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). Some of these patients relapse with KIT D816V-negative disease (20).…”

Section: Discussionmentioning

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%

“…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). However, anti-neoplastic effects of midostaurin are often transient (20,24).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, midostaurin can suppress growth of neoplastic MC in vivo in patients with advanced SM (20,24). However, anti-neoplastic effects of midostaurin are often transient (20,24). A remarkable phenomenon is that even in patients who have resistant disease or relapse, mediator-related symptoms improve or disappear during therapy (30).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Myeloproliferative Neoplasms: Chronic Myelogenous Leukemia, Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis

Tibes

Khera

Mesa

2012

Textbook of Uncommon Cancer

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Acute Myeloid Leukemia in Adults: Mast Cell Leukemia and Other Mast Cell Neoplasms

Stone

Schiffer

2017

Holland‐Frei Cancer Medicine

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Overview Acute myeloid leukemia (AML) is the most common variant of acute leukemia occurring in adults, comprising approximately 80% of acute leukemia cases diagnosed in individuals of age >20 years. Remarkable advances in transfusion medicine, treatment of infections, development of potent antiemetics, improved chemotherapeutic approaches, and increased use of safer allogeneic transplantation have led to an improved outcome at least in younger patients. Moreover, a more sophisticated understanding of pathophysiology, particularly in the area of genomics, may soon lead to less toxic, patient‐specific, and more effective therapies. At present, approximately 80% of younger (age <60 years) adults and 30%–50% of all older patients achieve complete remission (CR) defined as a morphologically normal bone marrow with reasonable neutrophil and platelet counts and no evidence of extramedullary disease. Varying with patient age and other biologic factors, 10–70% of these complete responders can be expected to achieve long‐term survival with the likelihood that most of these individuals are cured of their disease. However, AML is largely an intrinsically chemoresistant disease, the outcome in older adults has changed little, and the chemotherapeutic approach has remained stagnant.

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Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation

Cited by 222 publications

References 26 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

Myeloproliferative Neoplasms: Chronic Myelogenous Leukemia, Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis

Acute Myeloid Leukemia in Adults: Mast Cell Leukemia and Other Mast Cell Neoplasms

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