Imatinib binding and cKIT inhibition is abrogated by the cKIT kinase domain I missense mutation Val654Ala

McLean, Sean R.; Gana‐Weisz, Mali; Hartzoulakis, Basil; Frow, Richard; Whelan, Jeremy; Selwood, David L.; Boshoff, Chris

doi:10.1158/1535-7163.mct-05-0070

Cited by 66 publications

(54 citation statements)

References 47 publications

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“…The V654 side chain contacts imatinib directly in the crystal structure (38), and the loss of this hydrophobic interaction in the V654A mutant is predicted to decrease imatinib binding affinity. As published recently by others (32,44), our modeling confirmed this prediction (data not shown). In addition, the imatinib resistance of V654A c-KIT may be due in part to an enhanced ability to adapt the active conformation.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Roberts

Odell

Byrnes

et al. 2007

Molecular Cancer Therapeutics

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“…Our mutant KIT homology model (Val654Ala) showed that IM does not bind but MP470 and ATP do, with tight binding interactions. An alternate homology model of mutant KIT kinase domain (Val654Ala) based on the insulin RTK and Abl kinase showed that disruption of IM binding is due to lack of hydrophobic contacts with the diaminophenyl ring of IM (McLean et al, 2005). Our homology model, based on two c-Kit crystal structures, bound to ATP and not IM.…”

Section: Discussionmentioning

confidence: 90%

“…Overexpression of BAMBI inhibits the response of tumor cells to TGF-b and suggests that bcatenin interferes with TGF-b-mediated growth arrest by inducing the expression of BAMBI (Sekiya et al, 2004) that may contribute to an invasive GIST phenotype. Acquired mutations leading to IM resistance involve mis-sense mutations in the kinase domain of c-Kit, including Thr670Ile, Tyr823Asp and Val654Ala (Chen et al, 2005;McLean et al, 2005) that are sensitive to PKC412, a novel tyrosine kinase inhibitor (DebiecRychter et al, 2005). A study of 31 GIST patients were treated with IM and then underwent surgery: 13 were sensitive to IM, three had primary resistance and 15 had acquired resistance after initial benefit.…”

Section: Discussionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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“…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.

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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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Imatinib binding and cKIT inhibition is abrogated by the cKIT kinase domain I missense mutation Val654Ala

Cited by 66 publications

References 47 publications

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Resistance to c-KIT kinase inhibitors conferred by V654A mutation

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

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

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