Jak2 inhibitors: Rationale and role as therapeutic agents in hematologic malignancies

Sayyah, Jacqueline; Sayeski, Peter P.

doi:10.1007/s11912-009-0018-2

Cited by 26 publications

(18 citation statements)

References 50 publications

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“…Interestingly, the cumulative median survival of all patients (n = 11) presenting with a genetic aberration (mutRAS, FLT3-ITD, or JAK2 V617F, which are mutually exclusive) compared with those without (n = 29) was shorter (25 months versus not reached), and the difference reached statistical significance (P = 0.049). Given that specific inhibitors are currently under investigation for these aberrations (39,40), their detection is of clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Ricci

Fermo

Corti

et al. 2010

Clinical Cancer Research

126

103

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Purpose: The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML).Experimental Design: Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens.Results: MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive.Conclusions: Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring. Clin Cancer Res; 16(8); 2246-56. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Ricci

Fermo

Corti

et al. 2010

Clinical Cancer Research

126

103

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“…[12][13][14] The recent discovery of JAK V617F mutation in myeloproliferative disease leads to several JAK inhibitors in current clinical trials for myeloproliferative disorder, myelofibrosis, and leukemia. [15][16][17][18][19][20][21][22] Ruxolitinib, an inhibitor of JAK1 and JAK2, has been approved recently by the FDA as the first JAK inhibitor to treat myelofibrosis. 23 The role of constitutive JAK2 kinase activity in myeloproliferative neoplastic growth provides a rationale for investigating inhibition of JAK/STAT3 in solid tumors.…”

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confidence: 99%

MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells

Liu

Gaboriaud

Vougogianopoulou

et al. 2013

Cancer Biology & Therapy

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Janus kinase (JAK) and Src kinase are the two major tyrosine kinase families upstream of signal transducer and activator of transcription (STAT). Among the seven STAT family proteins, STAT3 is constitutively activated in many diverse cancers. Upon activation, JAK and Src kinases phosphorylate STAT3, and thereby promote cell growth and survival. MLS-2384 is a novel 6-bromoindirubin derivative with a bromo-group at the 6-position on one indole ring and a hydrophilic group at the 3'-position on the other indole ring. In this study, we investigated the kinase inhibitory activity and anticancer activity of MLS-2384. Our data from in vitro kinase assays, cell viability analyses, western blotting analyses, and animal model studies, demonstrate that MLS-2384 is a dual JAK/Src kinase inhibitor, and suppresses growth of various human cancer cells, such as prostate, breast, skin, ovarian, lung, and liver. Consistent with the inactivation of JAK and Src kinases, phosphorylation of STAT3 was inhibited in a dose-dependent manner in the cancer cells treated with MLS-2384. STAT3 downstream proteins involved in cell proliferation and survival, such as c-Myc and Mcl-1, are downregulated by MLS-2384 in prostate cancer cells, whereas survivin is downregulated in A2058 cells. In these two cancer cell lines, PARP is cleaved, indicating that MLS-2384 induces apoptosis in human melanoma and prostate cancer cells. Importantly, MLS-2384 suppresses tumor growth with low toxicity in a mouse xenograft model of human melanoma. Taken together, MLS-2384 demonstrates dual JAK/Src inhibitory activity and suppresses tumor cell growth both in vitro and in vivo. Our findings support further development of MLS-2384 as a potential small-molecule therapeutic agent that targets JAK, Src, and STAT3 signaling in multiple human cancer cells.

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“…Discovery of the JAK2 V617F mutation in myeloproliferative disease has prompted development of selective JAK2 inhibitors for treatment of hematologic disorders (11-13). Clinical studies of JAK2 inhibitors are currently ongoing (14-15). The role of constitutive JAK2 kinase activity in myeloproliferative neoplastic growth also provides the rationale for investigating JAK inhibitors in solid tumors.…”

Section: Introductionmentioning

confidence: 99%

6-Bromoindirubin-3′-Oxime Inhibits JAK/STAT3 Signaling and Induces Apoptosis of Human Melanoma Cells

et al. 2011

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Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated and contributes to malignant progression in various cancers. Janus kinases (JAKs) phosphorylate STAT3 in response to stimulation with cytokines or growth factors. The STAT3 signaling pathway has been validated as a promising target for development of anti-cancer therapeutics. Small-molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents. In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3'-oxime (6BIO) mediated growth inhibition of human melanoma cells and assessed 6BIO as an anticancer drug candidate. We found that 6BIO is a pan-JAK inhibitor that induced apoptosis of human melanoma cells. 6BIO directly inhibited JAK family kinase activity both in vitro and in cancer cells. Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both a dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, the anti-apoptotic protein Mcl-1 was down-regulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the AKT and MAPK signaling proteins were not inhibited in cells treated with 6BIO. Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma. Taken together, these results demonstrate that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induced tumor cell apoptosis. Our findings support further development of 6BIO as a potential anti-cancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells.

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Jak2 inhibitors: Rationale and role as therapeutic agents in hematologic malignancies

Cited by 26 publications

References 50 publications

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells

6-Bromoindirubin-3′-Oxime Inhibits JAK/STAT3 Signaling and Induces Apoptosis of Human Melanoma Cells

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