Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insulin treatment to control his blood glucose, but his HHS recurred. We discontinued the ceritinib for other side effects and noticed the HHS disappeared. Our findings suggest that ceritinib can cause HHS and that HHS may recur even after dose reductions.
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http://dx.doi.org/10.1007/s13340-020-00442-w | DOI Listing |
PLoS One
January 2025
Department of Basic Sciences, Bioethics and Human Life, Faculty of Human Medicine, University of Piura, Miraflores, Lima, Perú.
The anaplastic lymphoma kinase (ALK) oncoprotein plays a crucial role in non-small cell lung cancer (NSCLC) by activating signaling pathways involved in cell proliferation and survival through constitutive phosphorylation. While first-line crizotinib can regulate phosphorylation, mutations in the ALK gene can lead to resistance against ALK inhibitors (ALKi) such as ceritinib and alectinib. On the other hand, overexpression of BCL2, a protein involved in cell death regulation, has been observed in NSCLC and is considered a potential therapeutic target.
View Article and Find Full Text PDFChemistry
January 2025
Ulm University: Universitat Ulm, Organic Chemistry III, Albert-Einstein-Allee 11, 89081, Ulm, GERMANY.
The efficiency of kinase inhibiting cancer therapeutics is often limited by their poor solubility in water. PEGylation is one possible strategy to improve the solubility of the drug, however, means to cleave these after reaching the target is important to make use of the therapeutic effects of the native drug. Moreover, the length of the PEG chains will have an effect on the solubility and binding.
View Article and Find Full Text PDFBioorg Med Chem Lett
March 2025
Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address:
Targeted protein degradation has emerged as a novel therapeutic paradigm in drug discovery. Despite the FDA approval of anaplastic lymphoma kinase (ALK) inhibitors, the pursuit of compounds with enhanced potency and prolonged efficacy remains crucial to mitigate inevitable adverse effects. In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase.
View Article and Find Full Text PDFHum Cell
December 2024
Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
Giant cell tumor of bone (GCTB) is a rare osteolytic tumor composed of mononuclear stromal cells, macrophages, and osteoclast-like giant cells. While generally benign, GCTB has a high risk of local recurrence and can occasionally undergo malignant transformation or metastasis, posing significant clinical challenges. The primary treatment is complete surgical resection; however, effective management strategies for recurrent or advanced GCTB remain elusive, underscoring the need for further preclinical research.
View Article and Find Full Text PDFClin Pharmacol Ther
November 2024
Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, USA.
Direct measurement of spatial-temporal drug penetration and exposure in the human central nervous system (CNS) and brain tumors is difficult or infeasible. This study aimed to develop an innovative mechanistic modeling platform for quantitative prediction of spatial pharmacokinetics of systemically administered drugs in the human CNS and brain tumors. A nine-compartment CNS (9-CNS) physiologically-based pharmacokinetic model was developed to account for general anatomical structure and pathophysiological heterogeneity of the human CNS and brain tumors.
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