RRC ID 71947
著者 Grinkevitch V, Wappett M, Crawford N, Price S, Lees A, McCann C, McAllister K, Prehn J, Young J, Bateson J, Gallagher L, Michaut M, Iyer V, Chatzipli A, Barthorpe S, Ciznadija D, Sloma I, Wesa A, Tice DA, Wessels L, Garnett M, Longley DB, McDermott U, McDade SS.
タイトル Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists.
ジャーナル Mol Cancer Ther
Abstract Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death. High-throughput drug screening failed to identify genomic alterations associated with response to MEDI3039; however, transcriptomics analysis revealed striking association between MEDI3039 sensitivity and expression of core components of the extrinsic apoptotic pathway, most notably its main apoptotic effector caspase-8 in solid tumor cell lines. Further analyses of colorectal cell lines and patient-derived xenografts identified caspase-8 expression ratio to its endogenous regulator FLIP(L) as predictive of sensitivity to MEDI3039 in several major solid tumor types and a further subset indicated by caspase-8:MCL-1 ratio. Subsequent MEDI3039 combination screening of TRAIL-R2, caspase-8, FADD, and BID knockout models with 60 compounds with varying mechanisms of action identified two inhibitor of apoptosis proteins (IAP) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8:MCL-1 as potential predictive biomarkers for second-generation TRAIL-R2 agonists and loss of key effectors such as FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.
巻・号 21(4)
ページ 594-606
公開日 2022-4-1
DOI 10.1158/1535-7163.MCT-21-0532
PII 1535-7163.MCT-21-0532
PMID 35086954
PMC PMC7612587
MeSH Apoptosis CASP8 and FADD-Like Apoptosis Regulating Protein / genetics CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism Caspase 8 / genetics Cell Line, Tumor Genomics Humans Proto-Oncogene Proteins c-bcl-2* / metabolism TNF-Related Apoptosis-Inducing Ligand* / metabolism TNF-Related Apoptosis-Inducing Ligand* / pharmacology
IF 5.615
リソース情報
ヒト・動物細胞 PC-9(RCB4455)