Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

Tea Pemovska; Eric Johnson; Mika Kontro; Gretchen A Repasky; Jeffrey Chen; Peter Wells; Ciarán N Cronin; Michele McTigue; Olli Kallioniemi; Kimmo Porkka; Brion W Murray; Krister Wennerberg

doi:10.1038/nature14119

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

Tea Pemovska, Eric Johnson, Mika Kontro, Gretchen A Repasky, Jeffrey Chen, Peter Wells, Ciarán N Cronin, Michele McTigue, Olli Kallioniemi, Kimmo Porkka, Brion W Murray, Krister Wennerberg

145 Citations (Scopus)

Abstract

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

Original language	English
Journal	Nature
Volume	519
Issue number	7541
Pages (from-to)	102-5
Number of pages	4
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature14119
Publication status	Published - 5 Mar 2015
Externally published	Yes

Keywords

Angiogenesis Inhibitors/chemistry
Cell Line
Cell Proliferation/drug effects
Crystallization
Crystallography, X-Ray
Drug Repositioning
Drug Resistance, Neoplasm/genetics
Drug Screening Assays, Antitumor
Fusion Proteins, bcr-abl/antagonists & inhibitors
Humans
Imidazoles/chemistry
Indazoles/chemistry
Kidney Neoplasms/drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
Models, Molecular
Molecular Conformation
Phosphorylation/drug effects
Protein Binding
Protein Kinase Inhibitors/chemistry
Proto-Oncogene Proteins c-abl/antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nature14119

Cite this

@article{e11c18a886b54a639e10a9bf33f76eb8,

title = "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation",

abstract = "The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities. ",

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author = "Tea Pemovska and Eric Johnson and Mika Kontro and Repasky, {Gretchen A} and Jeffrey Chen and Peter Wells and Cronin, {Ciar{\'a}n N} and Michele McTigue and Olli Kallioniemi and Kimmo Porkka and Murray, {Brion W} and Krister Wennerberg",

year = "2015",

month = mar,

day = "5",

doi = "10.1038/nature14119",

language = "English",

volume = "519",

pages = "102--5",

journal = "Nature",

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T1 - Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

AU - Pemovska, Tea

AU - Johnson, Eric

AU - Kontro, Mika

AU - Repasky, Gretchen A

AU - Chen, Jeffrey

AU - Wells, Peter

AU - Cronin, Ciarán N

AU - McTigue, Michele

AU - Kallioniemi, Olli

AU - Porkka, Kimmo

AU - Murray, Brion W

AU - Wennerberg, Krister

PY - 2015/3/5

Y1 - 2015/3/5

N2 - The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

AB - The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

KW - Angiogenesis Inhibitors/chemistry

KW - Cell Line

KW - Cell Proliferation/drug effects

KW - Crystallization

KW - Crystallography, X-Ray

KW - Drug Repositioning

KW - Drug Resistance, Neoplasm/genetics

KW - Drug Screening Assays, Antitumor

KW - Fusion Proteins, bcr-abl/antagonists & inhibitors

KW - Humans

KW - Imidazoles/chemistry

KW - Indazoles/chemistry

KW - Kidney Neoplasms/drug therapy

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy

KW - Models, Molecular

KW - Molecular Conformation

KW - Phosphorylation/drug effects

KW - Protein Binding

KW - Protein Kinase Inhibitors/chemistry

KW - Proto-Oncogene Proteins c-abl/antagonists & inhibitors

KW - Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors

U2 - 10.1038/nature14119

DO - 10.1038/nature14119

M3 - Journal article

C2 - 25686603

SN - 0028-0836

VL - 519

SP - 102

EP - 105

JO - Nature

JF - Nature

IS - 7541

ER -

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

Abstract

Keywords

UN SDGs

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