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

Carmen D Herling; Nima Abedpour; Jonathan Weiss; Anna Schmitt; Ron Daniel Jachimowicz; Olaf Merkel; Maria Cartolano; Sebastian Oberbeck; Petra Mayer; Valeska Berg; Daniel Thomalla; Nadine Kutsch; Marius Stiefelhagen; Paula Cramer; Clemens-Martin Wendtner; Thorsten Persigehl; Andreas Saleh; Janine Altmüller; Peter Nürnberg; Christian Pallasch; Viktor Achter; Ulrich Lang; Barbara Eichhorst; Roberta Castiglione; Stephan C Schäfer; Reinhard Büttner; Karl-Anton Kreuzer; Hans Christian Reinhardt; Michael Hallek; Lukas P Frenzel; Martin Peifer

doi:10.1038/s41467-018-03170-7

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

Nat Commun. 2018 Feb 20;9(1):727. doi: 10.1038/s41467-018-03170-7.

Authors

Carmen D Herling¹, Nima Abedpour^{2

3}, Jonathan Weiss¹, Anna Schmitt^{1

3

4}, Ron Daniel Jachimowicz^{1

3

4}, Olaf Merkel^{1

4}, Maria Cartolano^{2

3}, Sebastian Oberbeck^{1

3

4

5}, Petra Mayer^{1

3

4

5}, Valeska Berg^{1

4}, Daniel Thomalla^{1

4}, Nadine Kutsch¹, Marius Stiefelhagen¹, Paula Cramer¹, Clemens-Martin Wendtner⁶, Thorsten Persigehl⁷, Andreas Saleh⁸, Janine Altmüller^{3

9}, Peter Nürnberg^{3

4

9}, Christian Pallasch^{1

3

4}, Viktor Achter¹⁰, Ulrich Lang^{10

11}, Barbara Eichhorst¹, Roberta Castiglione¹², Stephan C Schäfer¹², Reinhard Büttner¹², Karl-Anton Kreuzer¹, Hans Christian Reinhardt^{1

3

4}, Michael Hallek^{1

3

4}, Lukas P Frenzel^{1

4}, Martin Peifer^{13

14}

Affiliations

¹ Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany.
² Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
³ Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
⁴ Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
⁵ Laboratory of Lymphocyte Signaling and Oncoproteom, University of Cologne, 50931 Cologne, Germany.
⁶ Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, 80804 Munich, Germany.
⁷ Department of Radiology, Cologne University Hospital, 50937 Cologne, Germany.
⁸ Department of Diagnostic and Interventional Radiology and Pediatric Radiology, Städtisches Klinikum München Schwabing, 80804 Munich, Germany.
⁹ Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
¹⁰ Computing Center, University of Cologne, 50931 Cologne, Germany.
¹¹ Department of Informatics, University of Cologne, 50931 Cologne, Germany.
¹² Department of Pathology, University of Cologne, 50937, Cologne, Germany.
¹³ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [email protected].
¹⁴ Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. [email protected].

Abstract

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.

Publication types

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

MeSH terms

Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
Cyclin-Dependent Kinase Inhibitor p15 / genetics
Cyclin-Dependent Kinase Inhibitor p15 / metabolism
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18 / genetics
Cyclin-Dependent Kinase Inhibitor p18 / metabolism
Drug Resistance, Neoplasm*
Female
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
Male
Mutation
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Sulfonamides / therapeutic use*

Substances

Bridged Bicyclo Compounds, Heterocyclic
CDKN2A protein, human
CDKN2B protein, human
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
Neoplasm Proteins
Sulfonamides
BTG1 protein, human
venetoclax