Dasatinib

Lindauer, Markus; Hochhaus, Andreas

doi:10.1007/978-3-642-01222-8_7

Cited by 58 publications

(39 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most studied Src inhibitor, dasatinib, was developed as a drug that could reverse the acquired resistance of the BCR-ABL transcript to imatinib [77,78]. Most of the preclinical literature regarding dasatinib refers to this matter; however, there are preclinical studies trying to assess the direct effects of dasatinib in Src and the downstream effects on the cytoskeleton, which is complicated as it also blocks Lck, Fyn, Yes, Abl, c-Kit, PDGFR and EphA2 [79]. Specifi cally, dasatinib is able to abrogate the metastasis development in pancreas, sarcoma, mesothelioma, neuroblastoma, Ewing sarcoma, hormone-refractory prostate and breast cancer models [80][81][82][83][84][85][86].…”

Section: Src Inhibitorsmentioning

confidence: 98%

Targeting cytoskeleton reorganisation as antimetastatic treatment

2010

View full text Add to dashboard Cite

Metastatic relapse is responsible for 90% of cancer-related deaths. The process of distant spreading is a cascade of events that is regulated in a highly complex manner; one cellular phenomenon underlying all the events is cytoskeletal reorganisation. Despite the fact that the ability to leave the primary site and establish a viable mass in a distant site is a hallmark of cancer, targeting cytoskeletal reorganisation is an emerging field. In this review we describe the key signalling pathways controlling cytoskeletal reorganisation and the current targeted therapies against the "druggable" nodes. Finally, we discuss potential implications of trial design that can play a role in detecting the specific activity of this drug class.

show abstract

Section: Src Inhibitorsmentioning

confidence: 98%

Targeting cytoskeleton reorganisation as antimetastatic treatment

2010

View full text Add to dashboard Cite

show abstract

“…A milestone in the history of the treatment of CML remains allogenic hematopoietic stem cell transplantation (SCT), which was first introduced in the mid-1970s. 40 In the early 2000s, imatinib, which binds the ATP-binding site of the chimeric BCR-ABL1 TK in a competitive 42 This rather specific drug effect leads to broader inhibition of ABL independent of the protein conformation, making dasatinib more potent in advanced CML. Nilotinib (AMN107) exhibits a higher binding affinity and selectivity than imatinib.…”

Section: Treatment Of Chronic Myelogenous Leukemiamentioning

confidence: 99%

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

et al. 2014

View full text Add to dashboard Cite

417 IntroductionSeveral new targets have recently been identified in neoplastic mast cells (MCs), and various targeted drugs have been examined for their effectiveness in malignant MC disorders. However, most drugs, including new KIT D816V-blocking agents, such as midostaurin (PKC412), 1 and various BCR-ABL1 inhibitors known to block KIT-activity, such as imatinib or dasatinib, 2 have failed to achieve long-lasting remissions in aggressive systemic mastocytosis (ASM). There is a similar problem in Ph + CML, where imatinib-resistant patients do not reach molecular remission even when secondor third-line BCR-ABL1 tyrosine kinase inhibitors (TKIs) are applied, particularly in patients exhibiting the BCR-ABL1 T315I mutant.3 During disease progression, additional signal transduction pathways become activated in neoplastic cells. Among these, AKT and STAT5 are critical downstream signaling molecules constitutively phosphorylated imatinibresistant chronic myeloid leukemia (CML) and KIT D816V + SM. 4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs. 8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance. 9 Taken together, these observations strongly suggest that STAT5 and AKT are key drivers in drug-resistant CML and SM, and thus represent potential therapeutic targets. Small molecules targeting STAT5 or AKT may indeed be effective in these malignancies, especially in TKIs-resistant patients. However, inhibitors available today, such as pimozide or BP-1-108 for STAT5, 10,11 or perifosine for AKT,12 are neither specific nor potent enough to be applicable in clinical practice. Therefore, it seems important to develop compounds that specifically and potently target STAT5 and AKT. Mast cells and mastocytosis KIT and cytokine signaling in normal mast cellsMCs originate from bone marrow (BM)-derived hematopoietic stem cells (HSCs) that enter the peripheral tissues via the bloodstream and undergo maturation under the Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy open-access paper. doi:10.3324/haematol.2013.098442 Manuscript received on October 8, 2013. Manuscript accepted on December 20, 2013 Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of...

show abstract

“…Its capability to block ABL has allowed its use in the treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL; ref. 2). Dasatinib also inhibits other SRC family kinases (SFK), such as LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK (3).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Montero

Seoane²,

Ocaña³

et al. 2011

Clinical Cancer Research

256

202

View full text Add to dashboard Cite

Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) a and b, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. Clin Cancer Res; 17(17); 5546-52. Ó2011 AACR.

show abstract

Dasatinib

Cited by 58 publications

References 58 publications

Targeting cytoskeleton reorganisation as antimetastatic treatment

Targeting cytoskeleton reorganisation as antimetastatic treatment

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Contact Info

Product

Resources

About