Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia

• Published in: Nature communications Vol. 9; no. 1; pp. 727 - 8
• Main Authors: Herling, Carmen D., Abedpour, Nima, Weiss, Jonathan, Schmitt, Anna, Jachimowicz, Ron Daniel, Merkel, Olaf, Cartolano, Maria, Oberbeck, Sebastian, Mayer, Petra, Berg, Valeska, Thomalla, Daniel, Kutsch, Nadine, Stiefelhagen, Marius, Cramer, Paula, Wendtner, Clemens-Martin, Persigehl, Thorsten, Saleh, Andreas, Altmüller, Janine, Nürnberg, Peter, Pallasch, Christian, Achter, Viktor, Lang, Ulrich, Eichhorst, Barbara, Castiglione, Roberta, Schäfer, Stephan C., Büttner, Reinhard, Kreuzer, Karl-Anton, Reinhardt, Hans Christian, Hallek, Michael, Frenzel, Lukas P., Peifer, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 42/44; 49/23; 49/61; 631/114; 631/67/1990/283/1895; 96/109; Aberration; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer; Chronic lymphocytic leukemia; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-Dependent Kinase Inhibitor p18 - metabolism; Data processing; Drug Resistance, Neoplasm; Female; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Lymphatic leukemia; Male; multidisciplinary; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Patients; PD-L1 protein; Science; Science (multidisciplinary); Sulfonamides - therapeutic use; Therapeutic applications; Treatment resistance
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03170-7

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 ( PD-L1 ) that might pinpoint molecular aberrations offering structures for further therapeutic interventions. BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.