Molecular basis of the constitutive activity and STI571 resistance of Asp816Val mutant KIT receptor tyrosine kinase

Foster, Rowan Clare; Griffith, Renate; Ferrão, Paulo; Ashman, Leonie K.

doi:10.1016/j.jmgm.2004.04.003

Cited by 47 publications

(40 citation statements)

References 67 publications

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“…In GIST, mutations in the kinase domain of KIT are usually due to secondary point mutations (Kitamura and Hirotab, 2004) and can confer resistance to imatinib due to the altered conformation of the kinase which prevents drug interaction with the ATP binding pocket (Frost et al, 2002;Foster et al, 2004). The last case report in this series describes the treatment response seen in a patient with a D820Y mutation in exon 17 treated with sorafenib based on in vitro data predicting response .…”

Section: Discussionmentioning

confidence: 99%

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

et al. 2010

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BACKGROUND: Mutations in KIT are more frequent in specific melanoma subtypes, and response to KIT inhibition is likely to depend on the identified mutation. METHODS: A total of 32 patients with metastatic acral or mucosal melanoma were screened for mutations in KIT exons 11, 13 and 17. RESULTS: KIT mutations were found in 38% of mucosal and in 6% of acral melanomas. Three patients were treated with imatinib and one with sorafenib. All four patients responded to treatment, but three have since progressed within the brain. CONCLUSIONS: The observed clinical responses support further investigation of KIT inhibitors in metastatic melanoma, selected according to KIT mutation status.

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Section: Discussionmentioning

confidence: 99%

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

et al. 2010

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“…3 were serum starved for mutations that strongly favor the active conformation of the kinase domain can preclude drug binding by an indirect (conformational) mechanism. An example of this is the D816V substitution in the activation loop of the kinase domain of c-KIT (39). Such mutant receptors confer constitutive kinase activity and the ability to grow in the absence of added growth factors on normally factor-dependent cells (34,43).…”

Section: Discussionmentioning

confidence: 99%

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Roberts

Odell

Byrnes

et al. 2007

Molecular Cancer Therapeutics

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Certain mutations within c-KIT cause constitutive activation of the receptor and have been associated with several human malignancies. These include gastrointestinal stromal tumors (GIST), mastocytosis, acute myelogenous leukemia, and germ cell tumors. The kinase inhibitor imatinib potently inhibits c-KIT and is approved for treatment of GIST. However, secondary point mutations can develop within the kinase domain to confer resistance to imatinib and cause drug-resistant relapse. A common mutation, which results in a V654A substitution,

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“…1A). The most common cytoplasmic mutations in the JM domain and the TKD have been proposed to disrupt JM domain-mediated autoinhibition and favor an active kinase domain conformation (9). Oncogenic mutations in D5 of the ectodomain enhance the binding affinity of homotypic contacts, a step necessary for SCF-induced KIT activation (6,10,11).…”

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confidence: 99%

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

Shi

Sousa

Mandel-Bausch³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants. T he rapid growth in large cancer-sequencing efforts using exome and genome sequencing, as well as elucidation of copy number variations of many cancers, has provided important information about the genetic landscapes and somatic mutations that occur in most cancers. The various catalogs of somatic mutations, chromosomal translocations, and aberrant gene expressions have provided valuable insights about distinct patient populations exhibiting gain-of-function mutations that function as causal "driver" genes for subtypes of different cancers (1-3). These studies have revealed numerous oncogenic mutations in receptor tyrosine kinases (RTKs), which result in constitutive ligand-independent tyrosine kinase activation, cell transformation, and oncogenesis. Consequently, more than 20 kinase inhibitors and half a dozen therapeutic antibodies that block the action of RTKs or the action of critical components of their intracellular signaling pathways have been developed during the past decade and successfully applied in the clinic for treatment of many cancers.A variety of gain-of-function somatic mutations in the receptor tyrosine kinase KIT, including point mutations, in-frame deletions, and in-frame duplications, have been identified in human cancers, including gastro-intestinal-stromal tumors (GISTs), acute myeloid leukemia (AML), mast cell leukemia (MCL), and melanomas (4). Activation of the receptor tyrosine kinase KIT by its ligand stem cell factor (SCF) plays a central role in development of germ cells, hematopoietic cells, interstitial pacemaker cells, and other cells (5). Like other members of the type ΙΙΙ family of RTKs, the extracellular ligand binding domain of KIT contains five Ig-like modules (designated as D1, D2, D3, D4, and D5) connected to a single transmembrane helix, followed by a cytoplasmic region containing a regulatory juxtamembrane (JM) domain, a tyrosine kinase domain (TKD) with a kinase insert region and a C-terminal tail. Tyrosine autophosphorylation sites in the kinase insert region and the...

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Molecular basis of the constitutive activity and STI571 resistance of Asp816Val mutant KIT receptor tyrosine kinase

Cited by 47 publications

References 67 publications

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition

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