Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations

Wong, Stephane; McLaughlin, Jami; Cheng, Donghui; Zhang, Cheng; Shokat, Kevan M.; Witte, Owen N.

doi:10.1073/pnas.0407061101

Cited by 61 publications

(57 citation statements)

References 33 publications

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“…One striking observation was the failure of the T315A allele to phosphorylate any classical ABL substrates in vitro. This same threonine to alanine substitution has been engineered into BCR-ABL (and other kinases) to render the enzyme uniquely sensitive to artificial ATP analogues, thereby allowing highly specific identification of downstream substrates and assessment of kinase dependence (29,31,43,44). Our results suggest that the signaling characteristics of these mutant enzymes should be carefully evaluated as they may not always closely mimic the wild-type allele.…”

Section: Discussionmentioning

confidence: 99%

“…The final group contained four mutants (Y253H, M351T, F317L, and T315A) with substantially weaker transforming activity. Of note, the most weakly oncogenic mutation in this assay (T315A) is leukemogenic in mice (29) and has been linked to leukemia relapse in a dasatinibresistant CML patient in blast crisis. ¶ ¶ Because the increased kinase activity of p185 BCR-ABL has been implicated as the reason for increased potency (28,30), we hypothesized that the altered oncogenic fitness of the kinase inhibitor resistant BCR-ABL mutants would similarly be associated with a parallel change in kinase activity.…”

Section: Transformation Potency Of Most Kinase Inhibitor-resistant Bcmentioning

confidence: 99%

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Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Skaggs

Gorre²,

Рывкин³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

139

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The success of targeting kinases in cancer with small molecule inhibitors has been tempered by the emergence of drug-resistant kinase domain mutations. In patients with chronic myeloid leukemia treated with ABL inhibitors, BCR-ABL kinase domain mutations are the principal mechanism of relapse. Certain mutations are occasionally detected before treatment, suggesting increased fitness relative to wild-type p210 BCR-ABL. We evaluated the oncogenicity of eight kinase inhibitor-resistant BCR-ABL mutants and found a spectrum of potencies greater or less than p210. Although most fitness alterations correlate with changes in kinase activity, this is not the case with the T315I BCR-ABL mutation that confers clinical resistance to all currently approved ABL kinase inhibitors. Through global phosphoproteome analysis, we identified a unique phosphosubstrate signature associated with each drug-resistant allele, including a shift in phosphorylation of two tyrosines (Tyr 253 and Tyr 257 ) in the ATP binding loop (P-loop) of BCR-ABL when Thr 315 is Ile or Ala. Mutational analysis of these tyrosines in the context of Thr 315 mutations demonstrates that the identity of the gatekeeper residue impacts oncogenicity by altered P-loop phosphorylation. Therefore, mutations that confer clinical resistance to kinase inhibitors can substantially alter kinase function and confer novel biological properties that may impact disease progression.chronic myelogenous leukemia ͉ kinase inhibitor resistance ͉ phosphoproteomics ͉ imatinib ͉ dasatinib P oint mutations in the kinase domain of BCR-ABL are primarily responsible for resistance to the ABL inhibitor imatinib (Gleevec) in chronic myelogenous leukemia (CML) patients. The majority of imatinib-resistant BCR-ABL point mutations (of Ͼ50 distinct examples now reported clinically) impair drug binding by restricting flexibility of the enzyme, precluding adoption of the inactive conformation required for imatinib binding (1-4). The second generation Abl inhibitor dasatinib is effective against imatinib-resistant CML because it binds the BCR-ABL kinase domain regardless of activation loop conformation (5-7). As a result, the number of BCR-ABL mutations capable of conferring resistance to dasatinib is small and is limited almost exclusively to direct contact sites (8, 9). One mutation, T315I, confers resistance to imatinib, dasatinib, and the imatinib-related compound nilotinib (AMN-107) (10, 11).Although discovered in the context of drug resistance, there is growing evidence that these mutations may confer other fitness advantages to BCR-ABL. First, the T315I and E255K mutants were each detected by our group in imatinib-naïve CML blast crisis patients by direct sequencing of total BCR-ABL cDNA and are therefore estimated to account for at least 20% of the CML tumor burden in these patients (1). In addition, these and other kinase domain mutations have been identified before treatment in CML patients using mutation-specific quantitative PCR (12-18). Furthermore, the analogous mutation to T315I in the...

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Section: Discussionmentioning

confidence: 99%

Section: Transformation Potency Of Most Kinase Inhibitor-resistant Bcmentioning

confidence: 99%

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Skaggs

Gorre²,

Рывкин³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

139

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“…It has been reported that sole suppression of BCR-ABL activity is insufficient to eliminate BCR-ABL( þ ) KIT( þ )-expressing immature murine myeloid leukemic cells, and that therapeutic effectiveness of small-molecule drugs such as imatinib could be due to the inhibitor's ability to suppress other protein kinases in addition to the dominant target. 24 A need for inhibition of c-KIT kinase in addition to the BCR-ABL kinase to achieve growth inhibition of malignant stem cells could offer a possible explanation for why enhanced potency for BCR-ABL kinase inhibition by nilotinib does not lead to increased suppression of CML progenitor growth compared with imatinib, since nilotinib and imatinib have similar inhibitory effects on c-KIT. Downstream signaling mechanisms activated by the BCR-ABL TK in CML include the Ras/MAPK-, PI-3K/AKT-and STAT5-signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors

et al. 2008

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The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34þ cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term cultureinitiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells.

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“…Imatinib inhibits both BCR-ABL and c-KIT in hematopoietic progenitors, and this dual activity may in part account for its efficacy in CML. 53 Similarly, the drug SU5416 inhibits vascular endothelial growth factor receptors (VEGFR) in addition to FLT3 and c-KIT; among patients with c-KIT-positive AML, those who had a response to SU5416 had increased VEGF levels before treatment and decreased bone marrow microvasculature after treatment. 24 The response to this drug may thus be mediated both by inhibition of c-KIT signaling in the blasts and by blockade of VEGFR activation in the bone marrow microenvironment.…”

Section: Strategies To Target Tk S In Cancer Therapymentioning

confidence: 99%

Tyrosine Kinases as Targets for Cancer Therapy

Krause

Etten²

2005

N Engl J Med

1,219

821

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Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations

Cited by 61 publications

References 33 publications

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors

Tyrosine Kinases as Targets for Cancer Therapy

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