Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Jan A. Burger (), Dan A. Landau, Amaro Taylor-Weiner, Ivana Bozic, Huidan Zhang, Kristopher Sarosiek, Lili Wang, Chip Stewart, Jean Fan, Julia Hoellenriegel, Mariela Sivina, Adrian M. Dubuc, Cameron Fraser, Yulong Han, Shuqiang Li, Kenneth J. Livak, Lihua Zou, Youzhong Wan, Sergej Konoplev, Carrie Sougnez, Jennifer R. Brown, Lynne V. Abruzzo, Scott L. Carter, Michael J. Keating, Matthew S. Davids, William G. Wierda, Kristian Cibulskis, Thorsten Zenz, Lillian Werner, Paola Dal Cin, Peter Kharchencko, Donna Neuberg, Hagop Kantarjian, Eric Lander, Stacey Gabriel, Susan O’Brien, Anthony Letai, David A. Weitz, Martin A. Nowak, Gad Getz and Catherine J. Wu ()
Additional contact information
Jan A. Burger: MD Anderson Cancer Center
Dan A. Landau: Broad Institute
Amaro Taylor-Weiner: Broad Institute
Ivana Bozic: Program for Evolutionary Dynamics, Harvard University
Huidan Zhang: School of Engineering and Applied Sciences, Harvard University
Kristopher Sarosiek: Dana-Farber Cancer Institute
Lili Wang: Dana-Farber Cancer Institute
Chip Stewart: Broad Institute
Jean Fan: Center for Biomedical Informatics, Harvard Medical School
Julia Hoellenriegel: MD Anderson Cancer Center
Mariela Sivina: MD Anderson Cancer Center
Adrian M. Dubuc: Brigham and Women's Hospital and Harvard Medical School
Cameron Fraser: Dana-Farber Cancer Institute
Yulong Han: Bioinspired Engineering and Biomechanics Center, Xi’an Jiaotong University
Shuqiang Li: Fluidigm Corporation
Kenneth J. Livak: Fluidigm Corporation
Lihua Zou: Broad Institute
Youzhong Wan: Dana-Farber Cancer Institute
Sergej Konoplev: MD Anderson Cancer Center
Carrie Sougnez: Broad Institute
Jennifer R. Brown: Dana-Farber Cancer Institute
Lynne V. Abruzzo: MD Anderson Cancer Center
Scott L. Carter: Broad Institute
Michael J. Keating: MD Anderson Cancer Center
Matthew S. Davids: Dana-Farber Cancer Institute
William G. Wierda: MD Anderson Cancer Center
Kristian Cibulskis: Broad Institute
Thorsten Zenz: National Center for Tumors and German Cancer Research Center (DKFZ)
Lillian Werner: Biostatistics and Computational Biology, Dana-Farber Cancer Institute
Paola Dal Cin: Brigham and Women's Hospital and Harvard Medical School
Peter Kharchencko: Center for Biomedical Informatics, Harvard Medical School
Donna Neuberg: Biostatistics and Computational Biology, Dana-Farber Cancer Institute
Hagop Kantarjian: MD Anderson Cancer Center
Eric Lander: Broad Institute
Stacey Gabriel: Broad Institute
Susan O’Brien: MD Anderson Cancer Center
Anthony Letai: Dana-Farber Cancer Institute
David A. Weitz: School of Engineering and Applied Sciences, Harvard University
Martin A. Nowak: Program for Evolutionary Dynamics, Harvard University
Gad Getz: Broad Institute
Catherine J. Wu: Broad Institute

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Resistance to the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

Date: 2016
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DOI: 10.1038/ncomms11589

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