Signal Transduction and Targeted Therapy (Feb 2022)
Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia
- Qi Zhang,
- Bridget Riley-Gillis,
- Lina Han,
- Yanan Jia,
- Alessia Lodi,
- Haijiao Zhang,
- Saravanan Ganesan,
- Rongqing Pan,
- Sergej N. Konoplev,
- Shannon R. Sweeney,
- Jeremy A. Ryan,
- Yulia Jitkova,
- Kenneth Dunner,
- Shaun E. Grosskurth,
- Priyanka Vijay,
- Sujana Ghosh,
- Charles Lu,
- Wencai Ma,
- Stephen Kurtz,
- Vivian R. Ruvolo,
- Helen Ma,
- Connie C. Weng,
- Cassandra L. Ramage,
- Natalia Baran,
- Ce Shi,
- Tianyu Cai,
- Richard Eric Davis,
- Venkata L. Battula,
- Yingchang Mi,
- Jing Wang,
- Courtney D. DiNardo,
- Michael Andreeff,
- Jeffery W. Tyner,
- Aaron Schimmer,
- Anthony Letai,
- Rose Ann Padua,
- Carlos E. Bueso-Ramos,
- Stefano Tiziani,
- Joel Leverson,
- Relja Popovic,
- Marina Konopleva
Affiliations
- Qi Zhang
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Bridget Riley-Gillis
- AbbVie Inc.
- Lina Han
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Yanan Jia
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Alessia Lodi
- Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin
- Haijiao Zhang
- Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University
- Saravanan Ganesan
- Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131
- Rongqing Pan
- Dana-Farber Cancer Institute
- Sergej N. Konoplev
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center
- Shannon R. Sweeney
- Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin
- Jeremy A. Ryan
- Dana-Farber Cancer Institute
- Yulia Jitkova
- Princess Margaret Cancer Center
- Kenneth Dunner
- High Resolution Electron Microscopy Facility, The University of Texas MD Anderson Cancer Center
- Shaun E. Grosskurth
- AbbVie Inc.
- Priyanka Vijay
- AbbVie Inc.
- Sujana Ghosh
- AbbVie Inc.
- Charles Lu
- AbbVie Inc.
- Wencai Ma
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center
- Stephen Kurtz
- Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University
- Vivian R. Ruvolo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Helen Ma
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Connie C. Weng
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Cassandra L. Ramage
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Ce Shi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Tianyu Cai
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Richard Eric Davis
- Department of Lymphoma & Myeloma Research, The University of Texas MD Anderson Cancer Center
- Venkata L. Battula
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Yingchang Mi
- Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College
- Jing Wang
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center
- Courtney D. DiNardo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Jeffery W. Tyner
- Department of Cell, Developmental & Cancer Biology, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University
- Aaron Schimmer
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center
- Anthony Letai
- Dana-Farber Cancer Institute
- Rose Ann Padua
- Université de Paris, Institut de la Recherche Saint-Louis (IRSL), Inserm Unit 1131
- Carlos E. Bueso-Ramos
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center
- Stefano Tiziani
- Department of Nutritional Sciences, Department of Pediatrics, Department of Oncology, Dell Medical School, The University of Texas at Austin
- Joel Leverson
- AbbVie Inc.
- Relja Popovic
- AbbVie Inc.
- Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- DOI
- https://doi.org/10.1038/s41392-021-00870-3
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 13
Abstract
Abstract Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2–selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.
