BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study

Bubnoff, Nikolas von; Schneller, Folker; Peschel, Christian; Duyster, Justus

doi:10.1016/s0140-6736(02)07679-1

Cited by 428 publications

(315 citation statements)

References 13 publications

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“…This was perhaps best observed with STI-571 (Gleevec, imatinib mesylate, Novartis Pharma, Basel, Switzerland), a competitive inhibitor of the ATP-binding site of many kinases (Klejman et al, 2002). The wide clinical application of STI-571 is partially due to its ability to inhibit many kinases, including bcrabl, platelet-derived growth factor receptors, and c-Kit (Heinrich et al, 2000;McGary et al, 2002;von Bubnoff et al, 2002). The relatively nonspecific activity of STI-571 results in activity against Kit and the PDGFR in gastrointestinal stromal tumours (GIST) and against the PDGFR in hypereosinophilic syndrome.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

et al. 2005

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The phosphatidylinositol 3 0 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

et al. 2005

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“…The majority of patients with Ph þ ALL who relapse during the treatment with a TKI carry bcr-abl TKD mutations that display high IC 50 values in biochemical and cellular assays, 13,20,21 implying that they have a causal role in acquired imatinib resistance. 12 --19 Their role in primary resistance commonly observed in Ph þ ALL recurring after chemotherapy is uncertain, and it also remains to be determined when these mutations first develop.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Pfeifer

Lange²,

Wystub

et al. 2012

Leukemia

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Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph þ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n ¼ 26) or recurrent (n ¼ 65) Ph þ ALL, respectively (P ¼ ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph þ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical --translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph þ ALL.

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“…Retrospective analysis of pretreatment specimens using allele-specific oligonucleotide PCR (ASO-PCR) was able to demonstrate low levels of mutant cDNA in all four cases, indicating clonal selection. Similarly, von Bubnoff et al (2002) noted an increase in the proportion of mutant mRNA with sequential monitoring of relapsing patients.…”

Section: When Do Resistant Mutations Arise?mentioning

confidence: 90%

“…Despite good haematological response, in most cases relapse occurred early with a median survival of only 20 -30 weeks. Relapse is commonly associated with emergence of mutations in the BCR-ABL kinase (Gorre et al, 2001;von Bubnoff et al, 2002).…”

Section: Imatinib In Blast Crisis and Ph þ Acute Lymphoblastic Leukaementioning

confidence: 99%

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

Ross

Hughes

2004

Br J Cancer

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Over the past few years, a number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The leading drug in this area is imatinib mesylate, which targets ABL, KIT and PDGFR. It has been remarkably effective in the treatment of chronic myeloid leukaemia, although resistance remains a significant problem. From the imatinib experience in this setting, we present some principles of kinase inhibition that may have more general applicability in targeted anticancer therapy. It is clear that the identification of appropriate targets (activated kinases) and monitoring levels of response (to recognise emerging resistance) are essential to optimise clinical management.

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BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study

Cited by 428 publications

References 13 publications

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

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