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P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia.

Cang S, Liu D - J Hematol Oncol (2008)

Bottom Line: Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib.Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop.This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA. cangshundong@163.com

ABSTRACT
Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.

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Frequency of BCR-ABL P-loop mutations detected in 177 clinical specimens. The positions of the P-loop amino acid residues were indicated. M-methionine; L-leucine; G-glycine; Q-glutamine; Y-tyrosine. (adapted from ref. [19]).
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Figure 1: Frequency of BCR-ABL P-loop mutations detected in 177 clinical specimens. The positions of the P-loop amino acid residues were indicated. M-methionine; L-leucine; G-glycine; Q-glutamine; Y-tyrosine. (adapted from ref. [19]).

Mentions: As mentioned previously, the most widely studied and clinically dominant mechanisms of imatinib resistance involve acquired point mutations within the kinase domain of BCR-ABL. BCR-ABL mutants can be grouped based on imatinib sensitivity: sensitive (IC50 ≤ 1000 nM); intermediately sensitive (IC50 ≤ 3000 nM; ie, M244V, G250E, Q252H, F317L and E355G); and insensitive (IC50 > 3000 nM; ie, Y253F/H, E255K/V and T315I). The various mutations occur at different frequencies and confer different levels of imatinib resistance (Fig. 1) [19].


P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia.

Cang S, Liu D - J Hematol Oncol (2008)

Frequency of BCR-ABL P-loop mutations detected in 177 clinical specimens. The positions of the P-loop amino acid residues were indicated. M-methionine; L-leucine; G-glycine; Q-glutamine; Y-tyrosine. (adapted from ref. [19]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2567340&req=5

Figure 1: Frequency of BCR-ABL P-loop mutations detected in 177 clinical specimens. The positions of the P-loop amino acid residues were indicated. M-methionine; L-leucine; G-glycine; Q-glutamine; Y-tyrosine. (adapted from ref. [19]).
Mentions: As mentioned previously, the most widely studied and clinically dominant mechanisms of imatinib resistance involve acquired point mutations within the kinase domain of BCR-ABL. BCR-ABL mutants can be grouped based on imatinib sensitivity: sensitive (IC50 ≤ 1000 nM); intermediately sensitive (IC50 ≤ 3000 nM; ie, M244V, G250E, Q252H, F317L and E355G); and insensitive (IC50 > 3000 nM; ie, Y253F/H, E255K/V and T315I). The various mutations occur at different frequencies and confer different levels of imatinib resistance (Fig. 1) [19].

Bottom Line: Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib.Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop.This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA. cangshundong@163.com

ABSTRACT
Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.

Show MeSH
Related in: MedlinePlus