scholarly journals Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Le-Xun Wang ◽  
Jun-Dan Wang ◽  
Jia-Jie Chen ◽  
Bing Long ◽  
Ling-Ling Liu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cellular Senescence ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Aurora A Kinase ◽  
Aurora A ◽  
T315i Mutation

scholarly journals Simultaneous Inhibition of BCR-ABL1 Tyrosine Kinase and PAK1/2 Serine/Threonine Kinase Exerts Synergistic Effect against Chronic Myeloid Leukemia Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1544 ◽  
Author(s):  
Sylwia Flis ◽  
Ewelina Bratek ◽  
Tomasz Chojnacki ◽  
Marlena Piskorek ◽  
Tomasz Skorski
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Synergistic Effect ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Simultaneous Inhibition

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in the chronic phase (CML-CP). However, it is unlikely that they can completely “cure” the disease. This might be because some subpopulations of CML-CP cells such as stem and progenitor cells are resistant to chemotherapy, even to the new generation of TKIs. Therefore, it is important to look for new methods of treatment to improve therapeutic outcomes. Previously, we have shown that class I p21-activated serine/threonine kinases (PAKs) remained active in TKI-naive and TKI-treated CML-CP leukemia stem and early progenitor cells. In this study, we aimed to determine if simultaneous inhibition of BCR-ABL1 oncogenic tyrosine kinase and PAK1/2 serine/threonine kinase exert better anti-CML effect than that of individual treatments. PAK1 was inhibited by small-molecule inhibitor IPA-3 (p21-activated kinase inhibitor III), PAK2 was downregulated by specific short hairpin RNA (shRNA), and BCR-ABL1 tyrosine kinase was inhibited by imatinib (IM). The studies were conducted by using (i) primary CML-CP stem/early progenitor cells and normal hematopoietic counterparts isolated from the bone marrow of newly diagnosed patients with CML-CP and from healthy donors, respectively, (ii) CML-blast phase cell lines (K562 and KCL-22), and (iii) from BCR-ABL1-transformed 32Dcl3 cell line. Herein, we show that inhibition of the activity of PAK1 and/or PAK2 enhanced the effect of IM against CML cells without affecting the normal cells. We observed that the combined use of IM with IPA-3 increased the inhibition of growth and apoptosis of leukemia cells. To evaluate the type of interaction between the two drugs, we performed median effect analysis. According to our results, the type and strength of drug interaction depend on the concentration of the drugs tested. Generally, combination of IM with IPA-3 at the 50% of the cell kill level (EC50) generated synergistic effect. Based on our results, we hypothesize that IM, a BCR-ABL1 tyrosine kinase inhibitor, combined with a PAK1/2 inhibitor facilitates eradication of CML-CP cells.

scholarly journals Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Haematologica ◽  
2016 ◽  
Vol 102 (4) ◽  
pp. 719-727 ◽  
Author(s):  
Amir T. Fathi ◽  
Seth A. Wander ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Acute Myeloid

scholarly journals Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Leukemia ◽  
2008 ◽  
Vol 23 (3) ◽  
pp. 477-485 ◽  
Author(s):  
L L Remsing Rix ◽  
U Rix ◽  
J Colinge ◽  
O Hantschel ◽  
K L Bennett ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Global Target ◽  
Target Profile

scholarly journals Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 53-55 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Megan Breeden ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutation Detection ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Blast Phase ◽  
T315i Mutation ◽  
New Mutations

AbstractChronic myeloid leukemia (CML) with T315I mutation has been reported to have poor prognosis. We analyzed 27 patients with T315I, including 20 who developed T315I after imatinib failure (representing 11% of 186 patients with imatinib failure), and 7 of 23 who developed new mutations after second tyrosine kinase inhibitor (TKI). Median follow-up from mutation detection was 18 months. At the time of T315I detection, 10 were in chronic phase (CP), 9 in accelerated phase, and 8 in blast phase. Except for the lack of response to second TKIs (P = .002), there was no difference in patient characteristics and outcome between patients with T315I and those with other or no mutations. Patients in CP had a 2-year survival rate of 87%. Although the T315I mutation is resistant to currently available TKIs, survival of patients with T315I remains mostly dependent on the stage of the disease, with many CP patients having an indolent course.

Abstract 5389: Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation

2015 ◽  
Author(s):  
Soon-Sun Hong ◽  
Soo Jung Kim ◽  
Kyung Hee Jung ◽  
Hong Hua Yan ◽  
Zhenghuan Fang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Imatinib Resistant ◽  
T315i Mutation

scholarly journals Clonal Upregulation of Effector Cytotoxic T Lymphocytes in a Patient with Multiple Tyrosine Kinase Inhibitor-Refractory Chronic Myeloid Leukemia with Long-Term Survival

2021 ◽  
pp. 493-499
Author(s):  
Tatsuro Jo ◽  
Takahiro Sakai ◽  
Kaori Matsuzaka ◽  
Kazuhiro Noguchi ◽  
Shizuka Hayashi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Tyrosine Kinase Inhibitor ◽  
Cytotoxic T Lymphocytes ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Clonal Expansion ◽  
Molecular Response ◽  
T315i Mutation

We present the case of a patient with multiple tyrosine kinase inhibitor (TKI)-refractory chronic phase chronic myeloid leukemia (CP-CML) with a T315I mutation of abl1. Dasatinib, a second-generation TKI, was administered as the initial treatment but achieved neither a cytogenetic nor molecular response. A mutational analysis of abl1 revealed that the patient had a T315I mutation. The patient was then administered ponatinib, a third-generation TKI, which is thought to be effective against T315I; however, the complete blood counts became within normal limits, and neither a cytogenetic nor molecular response was achieved. However, the patient has maintained a healthy chronic phase (with no blast crises) for more than 5½ years since the diagnosis of CP-CML. T-cell receptor (TCR) repertoire analyses using peripheral blood revealed a remarkable clonal expansion of effector cytotoxic T lymphocytes (CTLs) that contained TCR V beta 13.6. We observed the clonal expansion of naïve CTLs with TCR V beta 13.6; however, no clonality was observed in the memory CTLs. The naïve and effector CTLs persisted at very high percentages since the seventh month after starting dasatinib. The CTLs could not have led to the molecular response; therefore, there might be plenty of CML stem cells remaining in the bone marrow. Therefore, although the CTLs might have prevented the disease from developing blast crises over more than 5 years, the CTLs might not have been able to become memory CTLs.

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