Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells

Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yūko; Ohyashiki, Kazuma

doi:10.18632/oncotarget.25985

Cited by 8 publications

(3 citation statements)

References 28 publications

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“…This hypothesis is supported by the observation that inhibition of ROCK or LIMK hyper-stabilizes mitotic spindles and impairs Aurora kinase A activation, suggesting the implication of the ROCK-LIMK-cofilin axis in Aurora kinase A activation via actin dynamics [16]. It was recently shown that Aurora kinase A is constitutively activated in BCR::ABL+ cells [22]. Furthermore, knockdown of Aurora kinase A enhanced activity of BCR::ABL-targeting TKIs, including leukemic cells harboring BCR::ABL mutations that conferred resistance to TKIs.…”

Section: Discussionmentioning

confidence: 81%

Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL)

Berrou

Dupont

Djamai

et al. 2022

JCM

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Ph+ (BCR::ABL+) B-ALL was considered to be high risk, but recent advances in BCR::ABL-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by BCR::ABL, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for BCR::ABL-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in BCR::ABL+ TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in BCR::ABL+ cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and BCR::ABL TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2Ako/BCR::ABL1+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with BCR::ABL-targeting TKIs, showing promising synergy that warrants further investigation.

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Section: Discussionmentioning

confidence: 81%

Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL)

Berrou

Dupont

Djamai

et al. 2022

JCM

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“…Tyrosine-protein phosphatase non-receptor type 11 (SHP2) plays an important role in CML since it is required to initiate and maintain BCR-ABL-mediated transformation, which is vital in leukemogenesis and hematopoiesis [ 27 ]). Auro-rakinase and mortalin are overexpressed in chronic myeloid leukemia, making them targets for inhibition, especially when conventional TKI inhibitors fail [ 28 , 29 ]). Vascular endothelial growth factor receptor (VEGFR)) and EGFR (vascular endothelial growth factor receptor epidermal) play key roles in leukemia cell proliferation and survival [ 30 , 31 ].…”

Section: Resultsmentioning

confidence: 99%

Lupane Triterpene Derivatives Improve Antiproliferative Effect on Leukemia Cells through Apoptosis Induction

et al. 2022

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Leukemia is one of the most frequent types of cancer. No effective treatment currently exists, driving a search for new compounds. Simple structural modifications were made to novel triterpenes isolated from Phoradendron wattii. Of the three resulting derivatives, 3α-methoxy-24-hydroxylup-20(29)-en-28-oic acid (T1m) caused a decrease in the median inhibitory concentration (IC50) on the K562 cell line. Its mode of action was apparently apoptosis, ROS generation, and loss of mitochondrial membrane potential (MMP). Molecular docking analysis showed T1m to produce lower binding energies than its precursor for the Bcl-2 and EGFR proteins. Small, simple, and viable modifications to triterpenes can improve their activity against leukemia cell lines. T1m is a potentially promising element for future research. Clarifying the targets in its mode of action will improve its applicability.

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“…Now, Alisertib (MLN8237), AT9283, and Danusertib (PHA-739358) show better results against CML and ALL patients that possess T3151 mutation. This may cause their use as off target agents in addition to other FDAapproved drugs [29].…”

Section: Bcr-abl As a Target For Therapymentioning

confidence: 99%

Molecular Pathogenesis and Treatment Strategies of Chronic Myeloid Leukemia (CML)

Khalid,

Riasat

2023

SJMS

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Chronic Myeloid Leukemia (CML) is a myeloproliferative disease diagnosed in bone marrow, arising from a chromosomal translocation between chromosomes 9 and 22, resulting in the formation of fusion oncogene BCR–ABL. The product of this fusion oncogene is a new oncoprotein bcr–abl which possesses abnormal tyrosine kinase activity. In response to this, abnormal signaling pathway activation occurs, leading to cell transformation. BCR–ABL oncogene could be targeted by tyrosine kinase inhibitors (TKIs) to delay or inhibit the disease progression. Imatinib is the first drug designed against CML but resistance to this has led to the development of the second- and third generations of inhibitors that are active against many types of BCR–ABL gene mutations. However, somehow, due to disease progression, TKIs do not remain as effective. There are three well-characterized phases of CML: The chronic phase (CP), the accelerated phase, and the terminal stage which is the blast crisis (BC) stage. In the CP of CML, mature granulocytes and myeloid precursors become aggregated majorly in the bone marrow and peripheral blood. The accelerated phase is marked by increased disease severity and an increase in progenitor/precursor cell number. In the BC stage, undifferentiated blast cells grow in number. Many patients with CML are diagnosed during the CP of the disease, so the survival rate of CML is high. However, 20% of CML patients proceed to advanced stages that result in drug resistance, intolerance, and mortality. So, for proper CML treatment, drugs are needed to target multiple BCR– ABL mutations, delay or stop disease progression, and overcome resistance caused by BCR–ABL independent mechanisms, especially during advanced phases of CML. Moreover, drugs could be developed to eradicate the stem cells of CML. These targets could be achieved by understanding mechanisms of disease progression, disease relapse, and drug resistance by utilizing high throughput molecular genetics, cell biology and immunology techniques.

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Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells

Cited by 8 publications

References 28 publications

Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL)

Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL)

Lupane Triterpene Derivatives Improve Antiproliferative Effect on Leukemia Cells through Apoptosis Induction

Molecular Pathogenesis and Treatment Strategies of Chronic Myeloid Leukemia (CML)

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