Ceritinib

Cooper, Michael; Chim, Helen; Chan, Hoyi; Durand, Cheryl

doi:10.1177/1060028014553619

Cited by 35 publications

(12 citation statements)

References 16 publications

(26 reference statements)

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“…The signaling accounting for stimulation of Ca 2+ entry in erythrocytes and for inhibition of Ca 2+ entry into blood platelets remains elusive. Ceritinib could be effective by inhibition of ALK [1-15]. The present observations do, however, not rule out involvement of mechanisms other than ALK.…”

Section: Discussionmentioning

confidence: 42%

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Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

Cao

Umbach

Bissinger

et al. 2018

Cell Physiol Biochem

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Background/Aims: The anaplastic lymphoma (tyrosine) kinase (ALK) inhibitor ceritinib triggers apoptosis of tumor cells and eryptosis of erythrocytes. Blood platelets may similarly enter a state resembling apoptosis, which could be triggered by activation with collagen related peptide (CRP). CRP-induced platelet apoptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the platelet surface and cell shrinkage, preceded by externalization of Ca²⁺ channel Orai1, increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), formation of reactive oxygen species (ROS), and caspase activation. The present study explored whether ceritinib triggers platelet apoptosis and/or modifies the CRP induced apoptosis. Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to ceritinib (1.5 µg/ml) without or with 2.5 – 15 min pretreatment with CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate cytosolic Ca²⁺-activity ([Ca²⁺]_i) from Fluo-3 fluorescence, ROS abundance from 2’,7’-dichlorodihydrofluorescein diacetate fluorescence, platelet degranulation from P-selectin abundance, integrin activation from α_IIbβ₃ integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. Results: In the absence of CRP, ceritinib slightly, but significantly decreased [Ca²⁺]_i without significantly modifying the other measured parameters. CRP significantly increased [Ca²⁺]_i, ROS abundance, P-selectin abundance, activated α_IIbβ₃ integrin, annexin-V-binding, caspase activity as well as aggregation and decreased cell volume, all effects significantly blunted in the presence of ceritinib. Conclusions: The present observations uncover a novel, unexpected effect of ceritinib, i.e. inhibition of CRP-induced platelet activation and apoptosis.

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Section: Discussionmentioning

confidence: 42%

“…The anaplastic lymphoma (tyrosine) kinase (ALK) inhibitor ceritinib is effective in the treatment of ALK positive non-small cell lung carcinoma [1-15]. Ceritinib has been shown to trigger apoptosis of tumor cells [16] and eryptosis, the suicidal erythrocyte death [17].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

Cao

Umbach

Bissinger

et al. 2018

Cell Physiol Biochem

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“… 25 In patient-derived models of acquired resistance to the tyrosine kinase inhibitor, MEK activation mutation and Src signaling were identified as other mechanisms that mediate ceritinib resistance. 36 , 39 Blockage of Src, or MEK, in these cells lines, while not effective when used alone, is able to restore sensitivity to ceritinib. Obtaining a tissue biopsy at the time of progression would be instrumental in identifying further mechanisms of ceritinib resistance.…”

Section: Therapeutic Challenges With Ceritinibmentioning

confidence: 87%

“…In addition to ALK, ceritinib also inhibits other tyrosine kinase receptors including the IGF1 (insulin-like growth factor 1) and insulin receptors, and at higher concentrations, ROS1. 36 , 37 Ceritinib may cause hyperglycemia likely as a result of insulin activity inhibition. Ceritinib has demonstrated activity in crizotinib-resistant tumor in xenografts models.…”

Section: Review Of Pharmacology Mode Of Action Efficacy and Toleramentioning

confidence: 99%

Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib

El-Osta¹,

Shackelford²

2015

PGPM

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The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%–7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib–ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naïve and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy.

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“…Notably, ceritinib (Zykadia®) is the rst FDA approved DAAPalogue for ALK/ROS1 inhibition [79][80][81] which has been described comprehensively elsewhere. [82][83][84][85][86][87] Interestingly, ceritinib being a member of DAAPalogues showed potency to overcome the gatekeeper mutation of L1196M which is still considered a resistance to crizotinib (non-DAAPalogue agent). In crizotinib, the existence of the polar-NH 2 (aromatic amine) substituent at C2-position of pyridine core is considered not to provide favorable interactions with a large lipophilic residue at the gatekeeper position, such as methionine.…”

Section: Rsc Advances Reviewmentioning

confidence: 99%

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

et al. 2018

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Ceritinib

Abstract: Ceritinib has activity in crizotinib-resistant and crizotinib-naïve patients and appears to be a viable alternative for ALK-positive NSCLC. Long-term data are needed to further define the role of ceritinib in the treatment of NSCLC.

Cited by 35 publications

References 16 publications

Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

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