Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.

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.

• Authors: Qi Zhang, Bridget Riley-Gillis, Lina Han, Yannan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N Konoplev, Shannon R Sweeney, Jeremy A Ryan, Yulia Jitkova, Kenneth Dunner Jr, 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
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 7 Issue 1 Pg. 51 (02 21 2022) ISSN: 2059-3635 [Electronic] England
• PMID: 35185150 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• ras Proteins
• venetoclax

Topics

• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism)
• MAP Kinase Signaling System (drug effects)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology)
• ras Proteins