Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin

2021 ◽  
Author(s):  
Delia I. Fernández ◽  
Alicia Veninga ◽  
Bibian M. E. Tullemans ◽  
Constance C. F. M. J. Baaten ◽  
Linsey J. F. Peters ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Synergistic Effects ◽  
Thrombus Formation ◽  
Type I ◽  
Glycoprotein Vi ◽  
Fibrin Formation ◽  
Increased Risk

Abstract Background Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation. Methods Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca2+]i, aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed. Results Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation. Conclusion Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.

Risk Factors for New Hypothyroidism During Tyrosine Kinase Inhibitor Therapy in Advanced Nonthyroidal Cancer Patients

Thyroid ◽  
2018 ◽  
Vol 28 (4) ◽  
pp. 437-444 ◽  
Author(s):  
Melissa G. Lechner ◽  
Chirag M. Vyas ◽  
Ole-Petter R. Hamnvik ◽  
Erik K. Alexander ◽  
P. Reed Larsen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Inhibitor Therapy ◽  
Tyrosine Kinase Inhibitor Therapy

scholarly journals Dabrafenib Induced Pancreatitis: A Rare Event During RAI- Refractory Treatment of Metastatic Papillary Thyroid Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A888-A889
Author(s):  
Khary Edwards ◽  
David McFadden ◽  
Sarimar N Agosto Salgado
Keyword(s):  
Acute Pancreatitis ◽  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Metastatic Melanoma ◽  
Cancer Patients ◽  
Papillary Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Papillary Thyroid ◽  
Thyroid Cancers

Abstract Dabrafenib, a BRAF selective tyrosine kinase inhibitor (TKI) has been associated with pancreatitis alone, and in combination with trametinib (a MEK pathway inhibitor). We report a case of dabrafenib induced acute pancreatitis in a patient undergoing treatment for metastatic papillary thyroid cancer (PTC). This adverse event has not been previously reported in thyroid cancer patients using dabrafenib. Case: A 61-year-old female with papillary thyroid cancer status post total thyroidectomy with pathology revealing right 7.6cm PTC with extrathyroidal extension and 13/72 metastatic lymph nodes. She received 100mCi of radioactive iodine (RAI). Ten months post-surgery, she underwent revision neck dissection with 3/36 nodes positive for metastatic disease and neck muscle invasion by PTC. Molecular testing demonstrated AKT1 and BRAFV600E mutations. Due to progressive neck and mediastinal tumors, recommendation was to proceed with systemic therapy. Initially started dabrafenib monotherapy; after 3 doses patient developed burning epigastric pain and fever. Examination revealed abdominal tenderness, elevated lipase at 2266 U/L (8-76U/L), mild hyperbilirubinemia and leukocytosis. CT abdomen/pelvis revealed peripancreatic fat stranding consistent with focal acute pancreatitis. No history of alcohol use. Dabrafenib was assessed to be culprit of pancreatitis; with immediate discontinuation of TKI and supportive management patient improved. At present patient is tolerating Lenvatinib therapy. BRAFV600E mutation occurs in 29-83% of thyroid cancers affecting growth, proliferation, survival, migration, and loss of tissue-specific differentiation via the intracellular MEK/ERK pathway1. RAI offers an important treatment modality for thyroid cancer patients, however patients with BRAFV600E are often poor responders or refractory to RAI1. Dabrafenib, a specific BRAFV600E tyrosine kinase inhibitor in combination with trametinib (a MEK inhibitor) is FDA approved for treatment BRAFV600E mutated anaplastic thyroid cancer; furthermore there is evidence on PTC responses including redifferentiation 2. Pancreatitis has been reported in <1% of dabrafenib treated patients as monotherapy and in combination with trametinib in unresectable or metastatic melanoma clinical trials. It was reported in 4% of patients in a NSCLC when used in combination with trametinib. Recurrent pancreatitis when dabrafenib was re-introduced at a lower dose has also been reported3. Furthermore, it was the cause of pancreatitis in a patient with metastatic melanoma 4 months into the treatment in combination with trametinib4. As this treatment option becomes increasingly utilized for metastatic or locally advanced anaplastic/papillary thyroid cancers, endocrinologists should be aware of the potential for dabrafenib induced pancreatitis during monotherapy use or in combination with trametinib.

Identification of a highly efficient dual type I/II FMS-like tyrosine kinase inhibitor that disrupts the growth of leukemic cells

2021 ◽  
Author(s):  
Mandy Beyer ◽  
Sven J. Henninger ◽  
Patricia S. Haehnel ◽  
Al-Hassan M. Mustafa ◽  
Ece Gurdal ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Leukemic Cells ◽  
Type I ◽  
Highly Efficient

scholarly journals Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces

2019 ◽  
Vol 20 (11) ◽  
pp. 2788 ◽  
Author(s):  
Natalie J. Jooss ◽  
Ilaria De Simone ◽  
Isabella Provenzale ◽  
Delia I. Fernández ◽  
Sanne L.N. Brouns ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Platelet Activation ◽  
Protein Tyrosine Kinase ◽  
Prediction Models ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Type I ◽  
Glycoprotein Vi ◽  
Collagen Peptides

Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2β1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.

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