Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia

  title={Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia},
  author={Mercedes E. Gorre and Charles L. Sawyers},
  journal={Current Opinion in Hematology},
Therapeutic use of the recently FDA-approved drug STI571 has been successful in the treatment of Philadelphia chromosome–positive leukemias. STI571 is a small molecule inhibitor with activity against BCR-ABL, the deregulated tyrosine kinase responsible for initiation and maintenance of the disease in the chronic phase of chronic myeloid leukemia (CML). Clinical trials demonstrated the ability of STI571 to induce remissions in patients with chronic phase CML with only rare relapses after 18… 

Imatinib mesylate (STI 571)--a new oral target therapy for chronic myelogenous leukemia (CML).

The publication provides an up-to-date review of the significance of cytogenetic abnormalities in chronic myelogenous leukemia (CML) and the development of a promising agent with specific molecular

Anticipating Clinical Resistance to Target-Directed Agents

To overcome resistance, several novel BCR-ABL inhibitors have been developed and are in clinical trials, though it is inevitable that resistance to second-generation inhibitors will occur as well.

Resistance to targeted therapy in chronic myelogenous leukemia.

Results from phase II/III trials suggest rates of resistance and relapse correlate with stage of disease and with the monitoring parameters: hematologic, cytogenetic, and molecular responses.

Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia

The most clinically promising anti-T315I therapies are summarized, including the exploitation of B CR-ABL1 kinase sites distant from the ATP-binding pocket to cripple the kinase activity of the enzyme and inhibiting signaling pathways downstream from BCR-ABl1.

High Affinity Molecules Disrupting GRB2 Protein Complexes as a Therapeutic Strategy for Chronic Myelogenous Leukaemia

This review briefly summarises the current understanding and therapy of CML and discusses in more detail basic laboratory research that attempts to target Grb2, an adaptor protein known to directly interact with the BCr portion of the Bcr-Abl fusion protein.

Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia

  • R. Ren
  • Biology, Medicine
    Nature Reviews Cancer
  • 2005
Although BCR–ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance.

New Bcr-Abl-independent mechanisms ofresistance to imatinib treatment in chronicmyelogenous leukaemia patients

The data on primary cells support the role of Shp1 in Ima resistance in patients, and the down-regulation of this gene to be related to the methylation level of SHP1 promoter, which is an important mechanism of ImA resistance.

New dosing schedules of dasatinib for CML and adverse event management

The clinical profile of dasatinib in imatinib-resistant and -intolerant patients is reviewed and clinical approaches for managing adverse events (AEs) are shared to ensure maximum patient benefit.

The Second Generation of BCR-ABL Tyrosine Kinase Inhibitors

The need for alternative or additional treatment for imatinib-resistant BCR-ABL-positive leukemia has guided the way to the design of a second generation of targeted therapies, which has resulted mainly in the development of novel small-molecule inhibitors such as AMN107, dasatinib, NS-187, and ON012380.

A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia.

A patient with chronic myelogenous leukemia in whom a minor population of imatinib-resistant cells were present at the time of diagnosis is described, and Cytogenetic analysis of bone marrow cells revealed acquired resistance toImatinib mesylate caused by kinase-domain mutations.



Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification

It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.

STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification.

Overexpression of the Bcr/Abl protein mediated through gene amplification is associated with and probably determines resistance of human leukemic cells to STI571 in vitro.

Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance.

It is concluded that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR -ABL.

Marked ploidy and BCR-ABL gene amplification in vivo in a patient treated with STI571

A patient who was enrolled on multinational trial of STI571 in interferon-resistant patients and 3 months later developed triploidy, as well as amplification of the BCR-ABL gene represents a major therapeutic advance in the management of CML.

Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571.

AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase, and molecules such as erythromycin that compete with STi571 for binding to AGP may enhance the therapeutic potential of this drug.

Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.

The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.

Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation.

Ph(+) ALL samples resistant to STI571 have a unique mutation Glu255Lys of BCR-ABL, which is within the motif important for forming the pocket of the ATP-binding site in ABL and it is highly conserved across species.

a 1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI 571

In vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571, and normal AGP, even at supraphysiological concentrations, did not block the effect of STi571 on K562-cell proliferation in vitro.

Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571.

The utility of this murine model of CML in the evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias is demonstrated and this improved murine chronic-phase CML model may be a useful tool for the study of STI571 resistance, CML progression, and the anti-CML immune response.