scholarly journals Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

2014 ◽  
Vol 21 (3) ◽  
pp. R247-R259 ◽  
Author(s):  
José O Alemán ◽  
Azeez Farooki ◽  
Monica Girotra
Keyword(s):  
Tyrosine Kinase ◽  
Targeted Therapies ◽  
Mineral Metabolism ◽  
Myelogenous Leukemia ◽  
Cytotoxic Agents ◽  
Imatinib Treatment ◽  
Vegf Inhibitors ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
Oncologic Treatment

Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.

A Population (Registry) Based Analysis of the Impact of Bcr-Abl Specific Tyrosine Kinase Inhibition on Survival after Diagnosis of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia..

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3237-3237
Author(s):  
A. Robert Turner ◽  
Joanne D Hewitt ◽  
Anmmd Kamruzzaman ◽  
Loree M. Larratt ◽  
Deborah A. Rusnak ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Alpha Interferon ◽  
Cell Transplant ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
The Impact ◽  
Philadelphia Chromosome Positive

Abstract Specific tyrosine kinase inhibition (TKI) of the bcr-abl fusion protein in Philadelphia chromosome positive chronic myelogenous leukemia (CML) was introduced into general use in 2000 after a plenary abstract presentation to ASH in December 1999. Here we report the impact of the use of TKI on survival of all patients with CML in a total population based registry in the province of Alberta in Canada where BMT has been in use since 1980, α interferon +/− cytarabine since 1990 and TKI since 2000. All therapies have been fully funded by the public health care system in Alberta. Alberta’s population in 2000 was 2.97 million. Prior to 2000, allogeneic stem cell transplant (BMT) was the only curative therapy available but its application was limited to a minority of patients with CML. Alpha interferon induced a cytogenetic remission in some CML and alpha interferon plus cytarabine prolonged survival in CML. CML AML n 5 yr survival % BMT n 5 yr survival % BMT *59% of deaths occurred in the first year after diagnosis in the 2000–06 cohort 1980–89 303 40% NA 540 13% NA 1990–99 276 48% 25 692 15% 13 2000–06 216 83%* 8 680 25% 16 p<0.0001 p<0.0001 A 5 year survival for CML (1980–89) of 40% is consistent with published data. The 48% 5 year survival for CML (1990–99) reflects the benefit of interferon. The 5 year survival of acute myelogenous leukemia (AML) in Alberta is provided for comparison to reflect general improvement in care. The proportion of AML patients who had a BMT did not significantly change while there was a significant reduction in numbers of CML transplanted in 2000–06. Transplant status did not significantly affect outcome in CML patients with 75% of non-BMT and 84% of BMT patients still alive at 5 years (p=0.08). In contrast, transplant status was statistically significant in AML, with 5 year survival of 49% in those treated with BMT, compared to 17% of those not transplanted (p<0.0001). The results of this study show that TKI therapy (primarily imatinib) has had a major impact on the outcome of CML treatment in the province of Alberta. Long term survival, >80%, has been achieved and it appears that almost all of these patients can look forward to a normal life expectancy without the need for BMT.

scholarly journals Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats

2004 ◽  
Vol 66 (5) ◽  
pp. 1766-1773 ◽  
Author(s):  
Vicente E. Torres ◽  
William E. Sweeney ◽  
Xiaofang Wang ◽  
Q.I. Qian ◽  
Peter C. Harris ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
Epidermal Growth

scholarly journals Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1904-1914 ◽  
Author(s):  
Hongfeng Yuan ◽  
Zhiqiang Wang ◽  
Ling Li ◽  
Hao Zhang ◽  
Hardik Modi ◽  
...  
Keyword(s):  
Stress Response ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Gene Knockout ◽  
Myelogenous Leukemia ◽  
Hematopoietic Progenitor Cells ◽  
Imatinib Treatment ◽  
Hematopoietic Progenitor ◽  
Response Gene ◽  
Stress Response Gene

Abstract The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but primary and acquired resistance of CML cells to the drug offset its efficacy. Molecular mechanisms for resistance of CML to tyrosine kinase inhibitors are not fully understood. In the present study, we show that BCR-ABL activates the expression of the mammalian stress response gene SIRT1 in hematopoietic progenitor cells and that this involves STAT5 signaling. SIRT1 activation promotes CML cell survival and proliferation associated with deacetylation of multiple SIRT1 substrates, including FOXO1, p53, and Ku70. Imatinib-mediated inhibition of BCR-ABL kinase activity partially reduces SIRT1 expression and SIRT1 inhibition further sensitizes CML cells to imatinib-induced apoptosis. Knockout of SIRT1 suppresses BCR-ABL transformation of mouse BM cells and the development of a CML-like myeloproliferative disease, and treatment of mice with the SIRT1 inhibitor tenovin-6 deters disease progression. The combination of SIRT1 gene knockout and imatinib treatment further extends the survival of CML mice. Our results suggest that SIRT1 is a novel survival pathway activated by BCR-ABL expression in hematopoietic progenitor cells, which promotes oncogenic transformation and leukemogenesis. Our findings suggest further exploration of SIRT1 as a therapeutic target for CML treatment to overcome resistance.

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