TY - JOUR
T1 - Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia
AU - Zhang, Qi
AU - Riley-Gillis, Bridget
AU - Han, Lina
AU - Jia, Yanan
AU - Lodi, Alessia
AU - Zhang, Haijiao
AU - Ganesan, Saravanan
AU - Pan, Rongqing
AU - Konoplev, Sergej N.
AU - Sweeney, Shannon R.
AU - Ryan, Jeremy A.
AU - Jitkova, Yulia
AU - Dunner, Kenneth
AU - Grosskurth, Shaun E.
AU - Vijay, Priyanka
AU - Ghosh, Sujana
AU - Lu, Charles
AU - Ma, Wencai
AU - Kurtz, Stephen
AU - Ruvolo, Vivian R.
AU - Ma, Helen
AU - Weng, Connie C.
AU - Ramage, Cassandra L.
AU - Baran, Natalia
AU - Shi, Ce
AU - Cai, Tianyu
AU - Davis, Richard Eric
AU - Battula, Venkata L.
AU - Mi, Yingchang
AU - Wang, Jing
AU - DiNardo, Courtney D.
AU - Andreeff, Michael
AU - Tyner, Jeffery W.
AU - Schimmer, Aaron
AU - Letai, Anthony
AU - Padua, Rose Ann
AU - Bueso-Ramos, Carlos E.
AU - Tiziani, Stefano
AU - Leverson, Joel
AU - Popovic, Relja
AU - Konopleva, Marina
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41392-021-00870-3
DO - 10.1038/s41392-021-00870-3
M3 - Article
C2 - 35185150
AN - SCOPUS:85125006295
SN - 2095-9907
VL - 7
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
IS - 1
M1 - 51
ER -