Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Rishu Agarwal; Yih Chih Chan; Constantine S. Tam; Tane Hunter; Dane Vassiliadis; Charis E. Teh; Rachel Thijssen; Paul Yeh; Stephen Q. Wong; Sarah Ftouni; Enid Y.N. Lam; Mary Ann Anderson; Christiane Pott; Omer Gilan; Charles C. Bell; Kathy Knezevic; Piers Blombery; Kathleen Rayeroux; Adrian Zordan; Jason Li; David C.S. Huang; Meaghan Wall; John F. Seymour; Daniel H.D. Gray; Andrew W. Roberts; Mark A. Dawson; Sarah Jane Dawson

doi:10.1038/s41591-018-0243-z

Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Rishu Agarwal
, Yih Chih Chan
, Constantine S. Tam
, Tane Hunter
, Dane Vassiliadis
, Charis E. Teh
, Rachel Thijssen
, Paul Yeh
, Stephen Q. Wong
, Sarah Ftouni
, Enid Y.N. Lam
, Mary Ann Anderson
, Christiane Pott
, Omer Gilan
, Charles C. Bell
, Kathy Knezevic
, Piers Blombery
, Kathleen Rayeroux
, Adrian Zordan
, Jason Li

David C.S. Huang, Meaghan Wall, John F. Seymour, Daniel H.D. Gray, Andrew W. Roberts, Mark A. Dawson^*, Sarah Jane Dawson

^*Corresponding author for this work

Peter Maccallum Cancer Centre
University of Melbourne
St. Vincent's Hospital Melbourne
Walter and Eliza Hall Institute of Medical Research
Kiel University
Victorian Cancer Cytogenetics Service
St Vincent's Institute of Medical Research

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1–p24.3 loss and/or mutations in components of the SWI–SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI–SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

Original language	English
Pages (from-to)	119-129
Number of pages	11
Journal	Nature medicine
Volume	25
Issue number	1
DOIs	https://doi.org/10.1038/s41591-018-0243-z
Publication status	Published - 1 Jan 2019

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Agarwal, R., Chan, Y. C., Tam, C. S., Hunter, T., Vassiliadis, D., Teh, C. E., Thijssen, R., Yeh, P., Wong, S. Q., Ftouni, S., Lam, E. Y. N., Anderson, M. A., Pott, C., Gilan, O., Bell, C. C., Knezevic, K., Blombery, P., Rayeroux, K., Zordan, A., ... Dawson, S. J. (2019). Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nature medicine, 25(1), 119-129. https://doi.org/10.1038/s41591-018-0243-z

@article{5785fcc941db4eed8d93d5dcc23be3b8,

title = "Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma",

abstract = "Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1–p24.3 loss and/or mutations in components of the SWI–SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI–SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.",

author = "Rishu Agarwal and Chan, \{Yih Chih\} and Tam, \{Constantine S.\} and Tane Hunter and Dane Vassiliadis and Teh, \{Charis E.\} and Rachel Thijssen and Paul Yeh and Wong, \{Stephen Q.\} and Sarah Ftouni and Lam, \{Enid Y.N.\} and Anderson, \{Mary Ann\} and Christiane Pott and Omer Gilan and Bell, \{Charles C.\} and Kathy Knezevic and Piers Blombery and Kathleen Rayeroux and Adrian Zordan and Jason Li and Huang, \{David C.S.\} and Meaghan Wall and Seymour, \{John F.\} and Gray, \{Daniel H.D.\} and Roberts, \{Andrew W.\} and Dawson, \{Mark A.\} and Dawson, \{Sarah Jane\}",

note = "Funding Information: The clinical study was funded by Abbvie and Janssen. The work included in this manuscript was funded by the Leukemia and Lymphoma Society (grant no. 0862-15 (S.-J.D., M.A.D., C.S.T., J.F.S.) and SCOR grant no. 11283-17 (A.W.R., D.C.S.H.)). We thank K. Doig, G. Arnau, T. Semple, T. Holloway and J. Carmody for advice and assistance with genomic sequencing, G. Lessene for providing A-1331852 and the following funders for fellowship, scholarship and grant support: CSL Centenary fellowship (S.-J.D.), Leukaemia Foundation Australia senior fellowship and Howard Hughes Medical Institute international research scholarship 55008729 (M.A.D.), NHMRC postgraduate scholarship 1114242 (R.A.) and HSANZ new investigator fellowship (R.A.), NHMRC fellowships (1089072 (C.E.T.), 1090236 (D.H.D.G.) and 1079560 (A.W.R.), NHMRC grant no. 1104549 (S.-J.D., M.A.D., C.S.T., J.F.S.) and programs 1113577, 1016701 (A.W.R., D.C.S.H.) and Leukemia and Lymphoma Society Independent Research Institutes Infrastructure Support Scheme grant no. 9000220 (R.T.), Snowdome Foundation (M.A.A.), Maddie Riewoldt{\textquoteright}s Vision 064728 (Y.-C.C.), Victorian State Government Operational Infrastructure Support grant and Cancer Council Victoria grant (nos. 1146518, 1102104) and the Peter MacCallum Cancer Foundation. Mass cytometry was performed in part at the Materials Characterization and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility, with support from the Victorian Comprehensive Cancer Centre. Funding Information: C.E.T., R.T., M.A.A., D.C.S.H., D.H.D.G. and A.W.R. are employees of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax. C.S.T., J.F.S. and A.W.R. received funding from Janssen and AbbVie to conduct the AIM clinical trial. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

day = "1",

doi = "10.1038/s41591-018-0243-z",

language = "English",

volume = "25",

pages = "119--129",

journal = "Nature medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

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}

Agarwal, R, Chan, YC, Tam, CS, Hunter, T, Vassiliadis, D, Teh, CE, Thijssen, R, Yeh, P, Wong, SQ, Ftouni, S, Lam, EYN, Anderson, MA, Pott, C, Gilan, O, Bell, CC, Knezevic, K, Blombery, P, Rayeroux, K, Zordan, A, Li, J, Huang, DCS, Wall, M, Seymour, JF, Gray, DHD, Roberts, AW, Dawson, MA & Dawson, SJ 2019, 'Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma', Nature medicine, vol. 25, no. 1, pp. 119-129. https://doi.org/10.1038/s41591-018-0243-z

TY - JOUR

T1 - Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

AU - Agarwal, Rishu

AU - Chan, Yih Chih

AU - Tam, Constantine S.

AU - Hunter, Tane

AU - Vassiliadis, Dane

AU - Teh, Charis E.

AU - Thijssen, Rachel

AU - Yeh, Paul

AU - Wong, Stephen Q.

AU - Ftouni, Sarah

AU - Lam, Enid Y.N.

AU - Anderson, Mary Ann

AU - Pott, Christiane

AU - Gilan, Omer

AU - Bell, Charles C.

AU - Knezevic, Kathy

AU - Blombery, Piers

AU - Rayeroux, Kathleen

AU - Zordan, Adrian

AU - Li, Jason

AU - Huang, David C.S.

AU - Wall, Meaghan

AU - Seymour, John F.

AU - Gray, Daniel H.D.

AU - Roberts, Andrew W.

AU - Dawson, Mark A.

AU - Dawson, Sarah Jane

N1 - Funding Information: The clinical study was funded by Abbvie and Janssen. The work included in this manuscript was funded by the Leukemia and Lymphoma Society (grant no. 0862-15 (S.-J.D., M.A.D., C.S.T., J.F.S.) and SCOR grant no. 11283-17 (A.W.R., D.C.S.H.)). We thank K. Doig, G. Arnau, T. Semple, T. Holloway and J. Carmody for advice and assistance with genomic sequencing, G. Lessene for providing A-1331852 and the following funders for fellowship, scholarship and grant support: CSL Centenary fellowship (S.-J.D.), Leukaemia Foundation Australia senior fellowship and Howard Hughes Medical Institute international research scholarship 55008729 (M.A.D.), NHMRC postgraduate scholarship 1114242 (R.A.) and HSANZ new investigator fellowship (R.A.), NHMRC fellowships (1089072 (C.E.T.), 1090236 (D.H.D.G.) and 1079560 (A.W.R.), NHMRC grant no. 1104549 (S.-J.D., M.A.D., C.S.T., J.F.S.) and programs 1113577, 1016701 (A.W.R., D.C.S.H.) and Leukemia and Lymphoma Society Independent Research Institutes Infrastructure Support Scheme grant no. 9000220 (R.T.), Snowdome Foundation (M.A.A.), Maddie Riewoldt’s Vision 064728 (Y.-C.C.), Victorian State Government Operational Infrastructure Support grant and Cancer Council Victoria grant (nos. 1146518, 1102104) and the Peter MacCallum Cancer Foundation. Mass cytometry was performed in part at the Materials Characterization and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility, with support from the Victorian Comprehensive Cancer Centre. Funding Information: C.E.T., R.T., M.A.A., D.C.S.H., D.H.D.G. and A.W.R. are employees of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax. C.S.T., J.F.S. and A.W.R. received funding from Janssen and AbbVie to conduct the AIM clinical trial. The remaining authors declare no competing interests. Publisher Copyright: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1–p24.3 loss and/or mutations in components of the SWI–SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI–SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

AB - Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1–p24.3 loss and/or mutations in components of the SWI–SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI–SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

UR - https://www.scopus.com/pages/publications/85056885060

U2 - 10.1038/s41591-018-0243-z

DO - 10.1038/s41591-018-0243-z

M3 - Article

C2 - 30455436

SN - 1078-8956

VL - 25

SP - 119

EP - 129

JO - Nature medicine

JF - Nature medicine

IS - 1

ER -

Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

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