Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Klug, Lillian R.; Kent, Jason D; Heinrich, Michael C.

doi:10.1016/j.pharmthera.2018.06.016

Cited by 40 publications

(37 citation statements)

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“…If the activation loop switch binds to the switch pocket, the kinase is in the on state and is active ( Figure 2) [29]. Oncogenic kinase mutations predominantly lead to disruption of one or more regulatory switch mechanisms, leading to dysregulated switch function and loss of normal, physiologic conformational control [30].…”

Section: Disease Overviewmentioning

confidence: 99%

Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib

et al. 2019

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Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501

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Section: Disease Overviewmentioning

confidence: 99%

Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib

et al. 2019

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“…KIT, also known as CD117, is a transmembrane receptor encoded by the KIT gene located on chromosome 4q12 that functions as the receptor for SCF. Together with other transmembrane receptors such as platelet-derived growth factors receptors α and β (PDGFRα and PDGFRβ), colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase 3 receptor (FLT3), KIT belongs to the class III family of receptor tyrosine kinases (RTKs), which serves a range of functions 18,19. KIT is expressed on multiple and diverse tissues, including hematopoietic stem and progenitor cells (HSPC), a subset of natural killer cells, epithelial cells in the skin adnexa, melanocytes, breast tissue, interstitial cells of Cajal (pacemaker cells in the gastrointestinal tract) and brain cells 20–22.…”

Section: Biology Of the Kit Receptormentioning

confidence: 99%

“…In the inactive form, catalytic triad DFG is in the “out” conformation, which permits the unphosphorylated JM domain to dock to the catalytic cleft, shielding the ATP-binding pocket. In the DFG-out conformation, aspartate (hydrophilic) is oriented away from the ATP binding pocket and acts to stabilize this inactive closed conformation through multiple hydrogen bonds 18…”

Section: Biology Of the Kit Receptormentioning

confidence: 99%

“…Physiological KIT activation begins when SCF binds to the N-terminal IgG-like motifs 2 and 3 of the KIT extracellular domain, which in turn activates the C-terminal IgG-like motifs 4 and 5 to initiate dimerization of the extracellular, transmembrane, and intracellular components 18,30,31. Extracellular SCF binding and receptor dimerization are followed by activation of low level kinase activity causing transphosphorylation of the JM domain at four tyrosines (primarily 568 and 570), which disrupts autoinhibitory interactions leading to destabilization of JM docking to AL 18. Upon JM phosphorylation, the JM moves away from the ATP binding pocket, the interactions of aspartate 816 are disrupted and the DFG motif reorients to the inward facing position (aspartate inward and phenylalanine outward), thereby allowing rotation of the N-lobe toward the C-lobe, triggering the AL to depart from the catalytic site and allowing for ATP binding.…”

Section: Biology Of the Kit Receptormentioning

confidence: 99%

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<p>Novel approaches to treating advanced systemic mastocytosis</p>

Gilreath¹,

Tchertanov²,

Deininger³

2019

CPAA

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Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KIT D816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KIT D816V . Midostaurin, a broad spectrum TKI with activity against KIT D816V , has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KIT D816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KIT D816V . Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KIT D816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.

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“…By virtue of these variable responses to imatinib observed in PDGFRA mutant GISTs, lately, different PDGFRA inhibitors have been entered into clinical studies. Among those showing better results, crenolanib was tested in a phase 2 trial and showed important preliminary clinical claims [41] ; these data have contributed to the initiation of a phase 3 randomized, placebo-controlled trial of crenolanib activity in PDGFRA D842V-mutant GISTs (NCT02847429) [42] . Table 1 summarizes correlation between exons harboring primary mutations and clinical response [43,44] .…”

Section: Kit/pdgfra Genotype and Clinical Outcomementioning

confidence: 99%

Somatic pharmacogenomics of gastrointestinal stromal tumor

Ravegnini¹,

Hrelia²,

Angelini³

2019

CDR

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Gastrointestinal stromal tumors (GISTs) are rare entities, which, however, represent the most common mesenchymal tumor of the gastrointestinal tract. The discovery of gain of function mutations on KIT and PDGFRA receptor genes led to a deep revolution in the knowledge of this tumor. This paved the way to the introduction of imatinib and other tyrosinekinase inhibitors (TKIs), which terrifically revolutionized the prognosis of GIST patients. Currently, it is well established that tumor mutational status is the main player in clinical outcome; however, with the research advances, it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes. For this reason, in the era of tailored/personalized medicine, each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.

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Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Cited by 40 publications

References 100 publications

Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib

Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib

<p>Novel approaches to treating advanced systemic mastocytosis</p>

Somatic pharmacogenomics of gastrointestinal stromal tumor

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