Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Christopher A. Eide; Matthew S. Zabriskie; Samantha L. Savage Stevens; Orlando Antelope; Nadeem A. Vellore; Hein Than; Anna Reister Schultz; Phillip Clair; Amber D. Bowler; Anthony D. Pomicter; Dongqing Yan; Anna V. Senina; Wang Qiang; Todd W. Kelley; Philippe Szankasi; Michael C. Heinrich; Jeffrey W. Tyner; Delphine Rea; Jean Michel Cayuela; Dong Wook Kim; Cristina E. Tognon; Thomas O'Hare; Brian J. Druker; Michael W. Deininger

doi:10.1016/j.ccell.2019.08.004

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Christopher A. Eide, Matthew S. Zabriskie, Samantha L. Savage Stevens, Orlando Antelope, Nadeem A. Vellore, Hein Than, Anna Reister Schultz, Phillip Clair, Amber D. Bowler, Anthony D. Pomicter, Dongqing Yan, Anna V. Senina, Wang Qiang, Todd W. Kelley, Philippe Szankasi, Michael C. Heinrich, Jeffrey W. Tyner, Delphine Rea, Jean Michel Cayuela, Dong Wook KimCristina E. Tognon, Thomas O'Hare, Brian J. Druker, Michael W. Deininger

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99 Scopus citations

Abstract

Most clinical BCR-ABL1 compound mutants are insensitive to current clinical tyrosine kinase inhibitors. Eide et al. show that adding asciminib, an allosteric inhibitor, to ponatinib, an ATP site inhibitor, effectively targets compound mutants and provides a potential mechanism for the collaborative effect.

Original language	English (US)
Pages (from-to)	431-443.e5
Journal	Cancer Cell
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.08.004
State	Published - Oct 14 2019

Keywords

ABL001
allosteric inhibitors
asciminib
chronic myeloid leukemia
compound mutation
ponatinib
targeted therapy

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2019.08.004

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Eide, C. A., Zabriskie, M. S., Savage Stevens, S. L., Antelope, O., Vellore, N. A., Than, H., Schultz, A. R., Clair, P., Bowler, A. D., Pomicter, A. D., Yan, D., Senina, A. V., Qiang, W., Kelley, T. W., Szankasi, P., Heinrich, M. C., Tyner, J. W., Rea, D., Cayuela, J. M., ... Deininger, M. W. (2019). Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants. Cancer Cell, 36(4), 431-443.e5. https://doi.org/10.1016/j.ccell.2019.08.004

Eide, CA, Zabriskie, MS, Savage Stevens, SL, Antelope, O, Vellore, NA, Than, H, Schultz, AR, Clair, P, Bowler, AD, Pomicter, AD, Yan, D, Senina, AV, Qiang, W, Kelley, TW, Szankasi, P, Heinrich, MC , Tyner, JW, Rea, D, Cayuela, JM, Kim, DW, Tognon, CE, O'Hare, T, Druker, BJ & Deininger, MW 2019, 'Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants', Cancer Cell, vol. 36, no. 4, pp. 431-443.e5. https://doi.org/10.1016/j.ccell.2019.08.004

@article{c3335de2981e436486169523bf004c3f,

title = "Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants",

abstract = "Most clinical BCR-ABL1 compound mutants are insensitive to current clinical tyrosine kinase inhibitors. Eide et al. show that adding asciminib, an allosteric inhibitor, to ponatinib, an ATP site inhibitor, effectively targets compound mutants and provides a potential mechanism for the collaborative effect.",

keywords = "ABL001, allosteric inhibitors, asciminib, chronic myeloid leukemia, compound mutation, ponatinib, targeted therapy",

author = "Eide, {Christopher A.} and Zabriskie, {Matthew S.} and {Savage Stevens}, {Samantha L.} and Orlando Antelope and Vellore, {Nadeem A.} and Hein Than and Schultz, {Anna Reister} and Phillip Clair and Bowler, {Amber D.} and Pomicter, {Anthony D.} and Dongqing Yan and Senina, {Anna V.} and Wang Qiang and Kelley, {Todd W.} and Philippe Szankasi and Heinrich, {Michael C.} and Tyner, {Jeffrey W.} and Delphine Rea and Cayuela, {Jean Michel} and Kim, {Dong Wook} and Tognon, {Cristina E.} and Thomas O'Hare and Druker, {Brian J.} and Deininger, {Michael W.}",

note = "Funding Information: We thank Novartis Pharmaceuticals for providing asciminib and nilotinib under Material Transfer Agreements. We thank all members of the Deininger, O'Hare, and Druker laboratories for technical assistance and/or valuable discussions. We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O{\textquoteright}H. and M.W.D.). M.C.H. is supported by a VA Merit Review Grant ( 2I01BX000338-05 ). D.Y. is supported by a Special Fellow Award from the Leukemia & Lymphoma Society . T.O{\textquoteright}H. is supported by the NIH /NCI ( R01 CA178397 ). M.W.D. is supported by the NIH ( HL082978-01 , 5 P01 CA049639-23 , and R01 CA178397 ). B.J.D. is an investigator for the Howard Hughes Medical Institute and is supported by the NIH/NCI ( R01 CA065823-21 ). Funding Information: We thank Novartis Pharmaceuticals for providing asciminib and nilotinib under Material Transfer Agreements. We thank all members of the Deininger, O'Hare, and Druker laboratories for technical assistance and/or valuable discussions. We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O'H. and M.W.D.). M.C.H. is supported by a VA Merit Review Grant (2I01BX000338-05). D.Y. is supported by a Special Fellow Award from the Leukemia & Lymphoma Society. T.O'H. is supported by the NIH/NCI (R01 CA178397). M.W.D. is supported by the NIH (HL082978-01, 5 P01 CA049639-23, and R01 CA178397). B.J.D. is an investigator for the Howard Hughes Medical Institute and is supported by the NIH/NCI (R01 CA065823-21). C.A.E. and M.S.Z. are co-first authors. B.J.D. and M.W.D. are co-senior authors. Conceptualization and Methodology, C.A.E. M.S.Z. T.O'H. C.E.T. B.J.D. and M.W.D.; Investigation, C.A.E. M.S.Z. S.L.S.S. O.A. N.A.V. H.T. A.R.S. P.C. A.D.B. A.D.P. D.Y. A.V.S. W.Q. and T.W.K.; Writing ? Original Draft, C.A.E. M.S.Z. and T.O'H.; Writing ? Review & Editing, C.A.E. M.S.Z. T.O'H. S.L.S.S. O.A. A.D.P. A.R.S. J.W.T. C.E.T. B.J.D. and M.W.D.; Funding Acquisition, T.O'H. C.E.T. B.J.D. and M.W.D.; Resources, T.W.K. P.S. M.C.H. J.W.T. D.R. J.M.-C. D.-W.K. T.O'H. B.J.D. and M.W.D.; Supervision, T.O'H. C.E.T. B.J.D. and M.W.D. M.W.D. served on advisory boards and as a consultant for Bristol-Myers Squibb, ARIAD, and Novartis and receives research funding from Bristol-Myers Squibb, Celgene, Novartis, and Gilead. B.J.D. potential competing interests??SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI BioPharma (inactive); Scientific Founder & Stock: MolecularMD; Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = oct,

day = "14",

doi = "10.1016/j.ccell.2019.08.004",

language = "English (US)",

volume = "36",

pages = "431--443.e5",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

AU - Eide, Christopher A.

AU - Zabriskie, Matthew S.

AU - Savage Stevens, Samantha L.

AU - Antelope, Orlando

AU - Vellore, Nadeem A.

AU - Than, Hein

AU - Schultz, Anna Reister

AU - Clair, Phillip

AU - Bowler, Amber D.

AU - Pomicter, Anthony D.

AU - Yan, Dongqing

AU - Senina, Anna V.

AU - Qiang, Wang

AU - Kelley, Todd W.

AU - Szankasi, Philippe

AU - Heinrich, Michael C.

AU - Tyner, Jeffrey W.

AU - Rea, Delphine

AU - Cayuela, Jean Michel

AU - Kim, Dong Wook

AU - Tognon, Cristina E.

AU - O'Hare, Thomas

AU - Druker, Brian J.

AU - Deininger, Michael W.

N1 - Funding Information: We thank Novartis Pharmaceuticals for providing asciminib and nilotinib under Material Transfer Agreements. We thank all members of the Deininger, O'Hare, and Druker laboratories for technical assistance and/or valuable discussions. We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O’H. and M.W.D.). M.C.H. is supported by a VA Merit Review Grant ( 2I01BX000338-05 ). D.Y. is supported by a Special Fellow Award from the Leukemia & Lymphoma Society . T.O’H. is supported by the NIH /NCI ( R01 CA178397 ). M.W.D. is supported by the NIH ( HL082978-01 , 5 P01 CA049639-23 , and R01 CA178397 ). B.J.D. is an investigator for the Howard Hughes Medical Institute and is supported by the NIH/NCI ( R01 CA065823-21 ). Funding Information: We thank Novartis Pharmaceuticals for providing asciminib and nilotinib under Material Transfer Agreements. We thank all members of the Deininger, O'Hare, and Druker laboratories for technical assistance and/or valuable discussions. We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O'H. and M.W.D.). M.C.H. is supported by a VA Merit Review Grant (2I01BX000338-05). D.Y. is supported by a Special Fellow Award from the Leukemia & Lymphoma Society. T.O'H. is supported by the NIH/NCI (R01 CA178397). M.W.D. is supported by the NIH (HL082978-01, 5 P01 CA049639-23, and R01 CA178397). B.J.D. is an investigator for the Howard Hughes Medical Institute and is supported by the NIH/NCI (R01 CA065823-21). C.A.E. and M.S.Z. are co-first authors. B.J.D. and M.W.D. are co-senior authors. Conceptualization and Methodology, C.A.E. M.S.Z. T.O'H. C.E.T. B.J.D. and M.W.D.; Investigation, C.A.E. M.S.Z. S.L.S.S. O.A. N.A.V. H.T. A.R.S. P.C. A.D.B. A.D.P. D.Y. A.V.S. W.Q. and T.W.K.; Writing ? Original Draft, C.A.E. M.S.Z. and T.O'H.; Writing ? Review & Editing, C.A.E. M.S.Z. T.O'H. S.L.S.S. O.A. A.D.P. A.R.S. J.W.T. C.E.T. B.J.D. and M.W.D.; Funding Acquisition, T.O'H. C.E.T. B.J.D. and M.W.D.; Resources, T.W.K. P.S. M.C.H. J.W.T. D.R. J.M.-C. D.-W.K. T.O'H. B.J.D. and M.W.D.; Supervision, T.O'H. C.E.T. B.J.D. and M.W.D. M.W.D. served on advisory boards and as a consultant for Bristol-Myers Squibb, ARIAD, and Novartis and receives research funding from Bristol-Myers Squibb, Celgene, Novartis, and Gilead. B.J.D. potential competing interests??SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI BioPharma (inactive); Scientific Founder & Stock: MolecularMD; Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/10/14

Y1 - 2019/10/14

N2 - Most clinical BCR-ABL1 compound mutants are insensitive to current clinical tyrosine kinase inhibitors. Eide et al. show that adding asciminib, an allosteric inhibitor, to ponatinib, an ATP site inhibitor, effectively targets compound mutants and provides a potential mechanism for the collaborative effect.

AB - Most clinical BCR-ABL1 compound mutants are insensitive to current clinical tyrosine kinase inhibitors. Eide et al. show that adding asciminib, an allosteric inhibitor, to ponatinib, an ATP site inhibitor, effectively targets compound mutants and provides a potential mechanism for the collaborative effect.

KW - ABL001

KW - allosteric inhibitors

KW - asciminib

KW - chronic myeloid leukemia

KW - compound mutation

KW - ponatinib

KW - targeted therapy

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UR - http://www.scopus.com/inward/citedby.url?scp=85072922152&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.08.004

DO - 10.1016/j.ccell.2019.08.004

M3 - Article

C2 - 31543464

AN - SCOPUS:85072922152

SN - 1535-6108

VL - 36

SP - 431-443.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Abstract

Keywords

ASJC Scopus subject areas

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