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Publications

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


Zhang Q, Riley-Gillis B, Han L, Jia Y, Lodi A, Zhang H, Ganesan S, Pan R, Konoplev SN, Sweeney SR, Ryan JA, Jitkova Y, Dunner K Jr, Grosskurth SE, Vijay P, Ghosh S, Lu C, Ma W, Kurtz S, Ruvolo VR, Ma H, Weng CC, Ramage CL, Baran N, Shi C, Cai T, Davis RE, Battula VL, Mi Y, Wang J, DiNardo CD, Andreeff M, Tyner JW, Schimmer A, Letai A, Padua RA, Bueso-Ramos CE, Tiziani S, Leverson J, Popovic R, Konopleva M.
Signal transduction and targeted therapy Feb 2022
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.

VIEW

Area

Heme

Institution Type

Academia

Indication / Modality

Acute Myleoid Leukemia (AML)

Goal of Study

Biomarker Discovery, Clonal Heterogeneity, Therapeutic Resistance

Key Genes

NRAS, KRAS

PAD Project

No

Analytes Assessed

SNV

Sample Storage

Fresh Frozen

Sample Prep

Whole Cells

Sample Type

Patient Material, PBMC

Tissue / Organ

Bone Marrow Aspirates

Species

Human

Panel Used

Custom

Proof Point Demonstrated

Clonality, Co-occurrence, Zygosity
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