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 - Funding Information:
This study is partially supported by NIH R01CA235622 (to MK). We acknowledge the Flow Cytometry and Cellular Imaging Core Facility at MD Anderson Cancer Center and Functional Proteomics Reverse Phase Protein Array Core, supported by NIH/NCI under award number P30CA016672. We acknowledge the Imaging platform of the IRSL for the microscopy (Universite de Paris). Editorial support was provided by Amy Ninetto of Scientific Publications, Research Medical Library, at MD Anderson Cancer Center. We acknowledge Robert Durruthy-Durruthy (MissionBio) for assisting with the single-cell-sequencing data analysis. This work was supported by research grant from AbbVie; by Cancer Center Support Grant from the NIH/NCI, P30 CA016672, and in part by the NCI Leukemia SPORE Career Development Award (CA100632) to VLB. The aligned sequencing data is deposited at SRA (submission no. SUB10899041).
Funding Information:
This study is partially supported by NIH R01CA235622 (to MK). We acknowledge the Flow Cytometry and Cellular Imaging Core Facility at MD Anderson Cancer Center and Functional Proteomics Reverse Phase Protein Array Core, supported by NIH/NCI under award number P30CA016672. We acknowledge the Imaging platform of the IRSL for the microscopy (Universite de Paris). Editorial support was provided by Amy Ninetto of Scientific Publications, Research Medical Library, at MD Anderson Cancer Center. We acknowledge Robert Durruthy-Durruthy (MissionBio) for assisting with the single-cell-sequencing data analysis. This work was supported by research grant from AbbVie; by Cancer Center Support Grant from the NIH/NCI, P30 CA016672, and in part by the NCI Leukemia SPORE Career Development Award (CA100632) to VLB. The aligned sequencing data is deposited at SRA (submission no. SUB10899041).
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
VL - 7
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
SN - 2095-9907
IS - 1
M1 - 51
ER -