Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Roberts, Kathryn G.; Odell, Adam F.; Byrnes, Ellen M.; Baleato, Rosa M.; Griffith, Renate; Lyons, A. Bruce; Ashman, Leonie K.

doi:10.1158/1535-7163.mct-06-0641

Cited by 75 publications

(46 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such differences are often observed with inhibitors of protein kinases (e.g., see refs. 28,29) and may have multiple causes. First, nonlinearities in the Western blots may have caused the IC 50 for tyrosine phosphorylation to appear at a higher concentration.…”

Section: Discussionmentioning

confidence: 99%

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Letard

Yang

Hanssens

et al. 2008

Molecular Cancer Research

159

241

View full text Add to dashboard Cite

In the current study, we examined the types and frequency of KIT mutations in mast cell tumors from 191 dogs. Sequencing of reverse transcription-PCR products revealed alterations in 50 (26.2%) of the dogs. Most mutations were in exon 11 (n = 32), and of these, most were internal tandem duplications (n = 25) between residues 571 and 590. Within exon 11, there were two hotspots for mutations at codons 555-559 and 571-590. In addition, nine dogs had mutations in exon 8 and eight had mutations in exon 9. We selected the two most common mutants and two representative exon 11 mutants for further analysis. When expressed in Ba/F3 cells, they were constitutively tyrosine phosphorylated and induced growth factor -independent cell proliferation. AG1296, a tyrosine kinase inhibitor, dose dependently inhibited both the tyrosine phosphorylation of these mutants and their induction of growth factor -independent proliferation. This study shows that activating mutations in not only exon 11 but also exons 8 and 9 are common in canine mast cell tumors. These results also show that Ba/F3 cells can be used for the direct characterization of canine KIT mutants, eliminating the need to make equivalent mutations in the mouse or human genes.

show abstract

Section: Discussionmentioning

confidence: 99%

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Letard

Yang

Hanssens

et al. 2008

Molecular Cancer Research

159

241

View full text Add to dashboard Cite

show abstract

“…The underlying mechanism of imatinib resistance varies between the different sites of secondary kinase mutations. On the basis of a number of in vitro studies, secondary mutations involving the ATP binding pocket were found to directly inhibit imatinib binding, especially the T670I "gatekeeper" mutation (46,49,50). This mutation is homologous to the resistance mutations of the "gatekeeper" threonine residues in BCR-ABL (T315I) and epidermal growth factor receptor (EGFR; T790M; refs.…”

Section: Imatinib Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors

Gramza

Corless

Heinrich

2009

Clinical Cancer Research

195

186

View full text Add to dashboard Cite

Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. The implementation of tyrosine kinase inhibitor (TKI) therapy has revolutionized the treatment of gastrointestinal stromal tumors (GIST). Currently, imatinib is approved for first-line therapy and sunitinib is approved for imatinib-resistant GIST. Unfortunately, similar to the experience using TKIs to treat other cancers, the emergence of drug-resistant GIST is becoming a problem for many patients, and there is a clear need for more agents and other approaches to the treatment of advanced GIST (1-5). Here, we review current knowledge on the response of GISTs to TKI therapy and the mechanisms by which resistance develops. Alternative targets and therapeutic options for patients with imatinib + sunitinib-resistant GIST are discussed.

show abstract

“…However, because acquired resistance is often observed in GIST and other cancers treated with TKIs or other targeted therapies, further rationally developed therapies against oncogenic KIT are necessary (12)(13)(14)(15)(16)(17). Moreover, it is not clear why anti-KIT mAbs that are ∼1,000-fold more potent than the TKI imatinib and 100-fold more potent than the TKI sunitinib in blocking the tyrosine kinase activity of WT KIT fail to block the activity of the oncogenic V560D KIT mutant.…”

mentioning

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.

View full text Add to dashboard Cite

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...

show abstract

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Cited by 75 publications

References 49 publications

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors

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

Contact Info

Product

Resources

About