scholarly journals Pulmonary hypertension with dasatinib and other tyrosine kinase inhibitors

2019 ◽  
Vol 9 (3) ◽  
pp. 204589401986570 ◽  
Author(s):  
Ashraf El-Dabh ◽  
Deepak Acharya
Keyword(s):  
Pulmonary Hypertension ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Right Heart Catheterization ◽  
Myelogenous Leukemia ◽  
Heart Catheterization ◽  
Early Therapy ◽  
Pulmonary Vasodilators ◽  
Small Series

Dasatinib and other tyrosine kinase inhibitors are commonly utilized in the management of chronic myelogenous leukemia. Pulmonary hypertension is an important adverse event associated with dasatinib. Mechanisms for pulmonary hypertension include pulmonary endothelial injury, apoptosis, and increased susceptibility to other triggers for pulmonary hypertension. The diagnosis is suspected based on symptoms, suggested by echocardiographic findings, and confirmed with right heart catheterization. Management includes discontinuation of dasatinib and initiation of pulmonary vasodilators. Persistent pulmonary hypertension is present in up to one third of patients after cessation of dasatinib. Other tyrosine kinase inhibitors, including bosutinib, lapatinib, and ponatinib have also been implicated in pulmonary hypertension in small series, although evidence for causation is less robust. A high index of suspicion, continued vigilance for pulmonary hypertension with long-term use, and early therapy are important in optimizing outcomes in this population.

scholarly journals Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 678-685 ◽  
Author(s):  
Cong Peng ◽  
Julia Brain ◽  
Yiguo Hu ◽  
Ami Goodrich ◽  
Linghong Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Myelogenous Leukemia ◽  
Leukemia Stem Cells

Abstract Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL–induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.

Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies

2002 ◽  
Vol 20 (6) ◽  
pp. 1692-1703 ◽  
Author(s):  
Michael C. Heinrich ◽  
Charles D. Blanke ◽  
Brian J. Druker ◽  
Christopher L. Corless
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lung Cancer ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Myelogenous Leukemia ◽  
Small Cell Lung

PURPOSE: Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis. In addition, paracrine or autocrine activation of this kinase has been postulated in numerous other malignancies, including small-cell lung cancer and ovarian cancer. In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies. MATERIALS AND METHODS: Studies were identified through a MEDLINE search, review of bibliographies of relevant articles, and review of abstracts from national meetings. RESULTS: Four tyrosine kinase inhibitors that have activity against KIT are currently being used in clinical trials, and one, STI571, has recently been approved by the United States Food and Drug Administration for treating patients with chronic myelogenous leukemia. The role of KIT inhibitors in treating KIT-positive malignancies is reviewed. CONCLUSION: Targeted therapy to inhibit the kinase activity of KIT is a rational approach to the treatment of KIT-positive malignancies. Two key factors are the potency of a given inhibitor and the relative contribution of KIT activation to the growth of the tumor. Given our current understanding of KIT activity in human malignancy, the best candidate diseases for treatment with KIT inhibitors are GIST, mastocytosis, seminoma and possibly some cases of AML. Additionally, KIT inhibitors may play an adjunctive role in diseases such as small-cell lung cancer, in which KIT activation is secondary to ligand binding rather than an acquired mutation.

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