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Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. 2016
Jan A Burger, and
Dan A Landau, and
Amaro Taylor-Weiner, and
Ivana Bozic, and
Huidan Zhang, and
Kristopher Sarosiek, and
Lili Wang, and
Chip Stewart, and
Jean Fan, and
Julia Hoellenriegel, and
Mariela Sivina, and
Adrian M Dubuc, and
Cameron Fraser, and
Yulong Han, and
Shuqiang Li, and
Kenneth J Livak, and
Lihua Zou, and
Youzhong Wan, and
Sergej Konoplev, and
Carrie Sougnez, and
Jennifer R Brown, and
Lynne V Abruzzo, and
Scott L Carter, and
Michael J Keating, and
Matthew S Davids, and
William G Wierda, and
Kristian Cibulskis, and
Thorsten Zenz, and
Lillian Werner, and
Paola Dal Cin, and
Peter Kharchencko, and
Donna Neuberg, and
Hagop Kantarjian, and
Eric Lander, and
Stacey Gabriel, and
Susan O'Brien, and
Anthony Letai, and
David A Weitz, and
Martin A Nowak, and
Gad Getz, and
Catherine J Wu
Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
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.
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