What question did this study set out to answer?

Determine the long-term impact of sequential ABL kinase inhibitor therapy on the emergence of resistant BCR-ABL mutations in patients with chronic myelogenous leukemia.

August 17, 2007Journal of Clinical InvestigationOpen Access

Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency

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Authors

NSNeil P. ShahReckitt Benckiser (United Kingdom)BSBrian J. SkaggsUniversity of California, Los Angeles SBSusan BranfordRoyal Adelaide Hospital

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Implication

Molecular analysis reveals sequential kinase inhibitor therapy selects for potent compound drug-resistant mutations in chronic myelogenous leukemia, suggesting upfront combination therapy is needed.

Key Points

Determine the long-term impact of sequential ABL kinase inhibitor therapy on the emergence of resistant BCR-ABL mutations in patients with chronic myelogenous leukemia.
Analyzed BCR-ABL kinase domain genotypes in patients with chronic myelogenous leukemia who relapsed after sequential treatment with imatinib and dasatinib.
Assessed in vitro drug sensitivity for re-treatment regimens and tested the oncogenic potency of compound mutations in transformation assays.
Evaluated the inhibitory activity of the Aurora kinase inhibitor VX-680 against common dasatinib-resistant mutations, including T315I and V299L.
All relapsed patients exhibited evolving resistant BCR-ABL kinase domain mutations, including 12 with the pan-resistant T315I mutation and 6 with mutations predicted to retain imatinib sensitivity.
Retreatment with imatinib or nilotinib succeeded in three patients, but sequential selection promoted compound mutations (two to three mutations in cis) that increased oncogenic potency relative to single mutants.
The kinase inhibitor VX-680 demonstrated cellular activity against both the pan-resistant T315I mutation and the recurrent dasatinib-resistant V299L mutation.

Cite This Study

Shah et al. (2007) studied this question.

synapsesocial.com/papers/6a1f28504d2ebb160c72a930 https://doi.org/10.1172/jci30890

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Implication

Molecular analysis reveals sequential kinase inhibitor therapy selects for potent compound drug-resistant mutations in chronic myelogenous leukemia, suggesting upfront combination therapy is needed.

Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency

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Implication

Key Points

Cite This Study

Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency

Discussion

Member takes

Implication

Key Points

Cite This Study

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