JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

Aranda-Tavío, Haidée; Recio, Carlota; Martín-Acosta, Pedro; Guerra-Rodríguez, Miguel; Brito‐Casillas, Yeray; Blanco, Rosa; Junco, Vanessa; León, Javier; Montero, Juan Carlos; Gandullo-Sánchez, Lucía; McNaughton‐Smith, Grant; Zapata, Juán M.; Pandiella, Atanasio; Amesty, Ángel; Estévez‐Braun, Ana; Fernández-Pérez, Leandro; Guerra, Borja

doi:10.1016/j.biopha.2021.112330

Cited by 4 publications

(6 citation statements)

References 61 publications

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“…The data reconfirmed that BCR/ABL1 has kinase activity. Many previous studies found a correlation between elevated STAT5 phosphorylation and imatinib resistance 33–35 . Akt protein hyperactivation leads to the activation of downstream cell processes and contributes to the TKIs resistance and apoptosis inhibition in CML 31 .…”

Section: Discussionmentioning

confidence: 93%

“…Many previous studies found a correlation between elevated STAT5 phosphorylation and imatinib resistance. [33][34][35] Akt protein hyperactivation leads to the activation of downstream cell processes and contributes to the TKIs resistance and apoptosis inhibition in CML. 31 These also support that BCR/ABL1ΔE7-8-9 is involved in drug resistance on the other hand.…”

Section: Discussionmentioning

confidence: 99%

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BCR/ABL1ΔE7‐8‐9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Tan

Zhang

Zhu

et al. 2022

Hematological Oncology

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In chronic myeloid leukemia (CML) patients, the involvement of the BCR/ABL1 isoform in tyrosine kinase inhibitors (TKIs) resistance has attracted lots of attention. In this work, a novel isoform that encoded truncated protein due to the deletion of ABL1 exon7, 8, and 9 was reported and named BCR/ABL1ΔE7‐8‐9 here. This isoform was detected only in 10.2% of CML patients with inadequate responses to TKIs. BCR/ABL1Δexon7‐8‐9 isoform promoted S phase cell proliferation and reduced the expression of fusion gene and ABL1 phosphorylation level more slowly than that of control cells after TKIs treatment. The novel isoform has the qualities of a functional tyrosine kinase, localized in the cytoplasm, and could not be imported into the nucleus by TKIs. These results indicated that BCR/ABL1Δexon7‐8‐9 showed poorer sensitivity to imatinib and nilotinib than wild‐type BCR/ABL1. According to molecular docking studies, nilotinib and imatinib present different binding sites and have a lower binding capacity with BCR/ABL1ΔE7‐8‐9 protein than the wild type. Our findings suggested that the novel isoform BCR/ABL1ΔE7‐8‐9 may contribute to TKIs resistance in CML due to its weakened TKIs binding ability. It enriched the mechanism of spliceosome involved in TKIs resistance. Monitoring the expression of BCR/ABL1ΔE7‐8‐9 helps guide the treatment of CML patients in the clinic.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

BCR/ABL1ΔE7‐8‐9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Tan

Zhang

Zhu

et al. 2022

Hematological Oncology

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“…Another historically posed challenge linked to the clinical use of 4-OHTAM and other SERMs is the generation of endocrine resistance mainly due to the use of high doses or prolonged treatments [ 7 , 65 ]. In this sense, drug combination may allow the reaching of synergistic pharmacological effects that reduce drug toxicity, resistance and/or increase drug efficacy [ 43 , 67 ]. Hence, to determine whether compounds 32 and/or 35 enhance the antitumoral effects of 4-OHTAM in ER+ BC cells, dose-response synergistic assays combining each compound with 4-OHTAM were performed ( Figure 15 A).…”

Section: Resultsmentioning

confidence: 99%

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

Guerra-Rodríguez

López-Rojas

Amesty

et al. 2022

Cancers

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Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.

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“…The Philadelphia chromosome, a chimeric chromosome resulting from a reciprocal translocation of the Abelson murine viral homologue 1 ( ABL1 ) gene on chromosome 9 and the breakpoint cluster region ( BCR ) gene on chromosome 22, has been implicated as a major factor in the development of CML 1 . The Philadelphia chromosome generates BCR::ABL1 protein, which is positive in approximately 95% of CML patients 2 . BCR::ABL1 protein constitutively activates, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphoinositide 3‐kinase (PI3K)/Akt, and mitogen‐activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal‐regulated kinase 1/2 (ERK1/2) pathways, which are involved in CML cell proliferation and survival 2 .…”

Section: Introductionmentioning

confidence: 99%

“…The Philadelphia chromosome generates BCR::ABL1 protein, which is positive in approximately 95% of CML patients 2 . BCR::ABL1 protein constitutively activates, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphoinositide 3‐kinase (PI3K)/Akt, and mitogen‐activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal‐regulated kinase 1/2 (ERK1/2) pathways, which are involved in CML cell proliferation and survival 2 . BCR::ABL1‐dependent activation of Src kinase also contributes to the pathogenesis of CML 3 .…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells

et al. 2023

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JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

Cited by 4 publications

References 61 publications

BCR/ABL1ΔE7‐8‐9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

BCR/ABL1ΔE7‐8‐9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells

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