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

Nat Med. 2019 Jan;25(1):119-129. doi: 10.1038/s41591-018-0243-z. Epub 2018 Nov 19.

Authors

Rishu Agarwal^#^{1

2}, Yih-Chih Chan^#^{1

2}, Constantine S Tam^{3

4

5}, Tane Hunter^{1

2}, Dane Vassiliadis^{1

2}, Charis E Teh^{6

7}, Rachel Thijssen^{6

7}, Paul Yeh^{1

2

3}, Stephen Q Wong¹, Sarah Ftouni¹, Enid Y N Lam^{1

2}, Mary Ann Anderson^{3

6

7}, Christiane Pott⁸, Omer Gilan^{1

2}, Charles C Bell^{1

2}, Kathy Knezevic¹, Piers Blombery^{1

3}, Kathleen Rayeroux⁹, Adrian Zordan⁹, Jason Li^{1

2}, David C S Huang^{6

7}, Meaghan Wall^{5

9

10}, John F Seymour^{2

3}, Daniel H D Gray^{6

7}, Andrew W Roberts^{3

6

7

11}, Mark A Dawson^{12

13

14

15}, Sarah-Jane Dawson^{16

17

18}

Affiliations

¹ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
² Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
³ Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Department of Haematology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
⁵ Department of Medicine, St. Vincent's Hospital, Melbourne, Victoria, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁷ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁸ University Hospital of Schleswig-Holstein, Kiel, Germany.
⁹ Victorian Cancer Cytogenetics Service, Melbourne, Victoria, Australia.
¹⁰ St. Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
¹¹ Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
¹² Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].
¹³ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. [email protected].
¹⁴ Department of Haematology, Royal Melbourne Hospital & Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].
¹⁵ Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia. [email protected].
¹⁶ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].
¹⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. [email protected].
¹⁸ Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia. [email protected].

^# Contributed equally.

PMID: 30455436
DOI: 10.1038/s41591-018-0243-z

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / metabolism
Adenine / analogs & derivatives
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
Cell Line, Tumor
Chromatin / metabolism
Chromosomal Proteins, Non-Histone / genetics*
Chromosomal Proteins, Non-Histone / metabolism
Circulating Tumor DNA / genetics
Cohort Studies
DNA Helicases / metabolism
Drug Resistance, Neoplasm / genetics*
Genome, Human
Humans
Lymphoma, Mantle-Cell / drug therapy*
Lymphoma, Mantle-Cell / genetics*
Models, Biological
Mutation / genetics*
Nuclear Proteins / metabolism
Piperidines
Prognosis
Pyrazoles / therapeutic use*
Pyrimidines / therapeutic use*
Sulfonamides / therapeutic use*
Transcription Factors / genetics*
Transcription Factors / metabolism
Treatment Outcome
bcl-X Protein / metabolism

Substances

ATF3 protein, human
Activating Transcription Factor 3
Bridged Bicyclo Compounds, Heterocyclic
Chromatin
Chromosomal Proteins, Non-Histone
Circulating Tumor DNA
Nuclear Proteins
Piperidines
Pyrazoles
Pyrimidines
SWI-SNF-B chromatin-remodeling complex
Sulfonamides
Transcription Factors
bcl-X Protein
ibrutinib
SMARCA4 protein, human
DNA Helicases
Adenine
venetoclax

Abstract

Publication types

MeSH terms

Substances

Grants and funding