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.

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Fig. 1: Genomic characterization of MCL patients enrolled in the AIM clinical trial.
Fig. 2: Modeling resistance to ibrutinib and venetoclax.
Fig. 3: Genomic characterization of a non-AIM patient with MCL.
Fig. 4: Bcl-xL inhibition overcomes ibrutinib and venetoclax resistance.
Fig. 5: SMARCA4 regulates the expression of ATF3.
Fig. 6: ctDNA analysis allows monitoring of treatment response and emerging resistance in patients treated with ibrutinib and venetoclax.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. The sequencing data that supports the findings of this study has been deposited into the sequence read archive, which is hosted by the National Centre for Biotechnology Information. The BioProject accession number is PRJNA489753.

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Acknowledgements

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.

Author information

R.A. and Y.-C.C. performed the majority of the experiments, helped develop the overall concept behind the analysis, and helped write the manuscript. T.H., D.V., C.E.T., R.T., P.Y., S.Q.W., S.F., E.Y.N.L., M.A.A., C.P., O.G., C.C.B., K.K., P.B., K.R., A.Z., J.L., M.W. and D.H.D.G. contributed to data analysis. D.C.S.H. provided critical reagents. C.S.T., J.F.S. and A.W.R initiated and conducted the AIM clinical trial, provided patient data, facilitated biospecimen collection and contributed to the interpretation of the research findings. S.-J.D. and M.A.D. developed the overall concept behind the study, supervised the experiments, analyzed the data and wrote the manuscript.

Correspondence to Mark A. Dawson or Sarah-Jane Dawson.

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Competing interests

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.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 4, 6 and 8–11

Reporting Summary

Supplementary Table 1

Clinicopathological and molecular characteristics of MCL cases on AIM study

Supplementary Table 2

Clinical samples used for tumor and plasma whole-exome sequencing (WES), targeted sequencing (TS) and low-coverage whole-genome sequencing (LC-WGS)

Supplementary Table 3

All variants identified from whole-exome sequencing

Supplementary Table 5

Differential expressed genes of RNA-seq data comparing SMARCA4 knockdown in Z-138 cells to control

Supplementary Table 7

List of primers used for targeted amplicon sequencing

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