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Molecular cancer therapeutics
04 01, 2022;21 (4): 594-606.

Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists.

Vera Grinkevitch, Mark Wappett, Nyree Crawford, Stacey Price, Andrea Lees, Christopher McCann, Katherine McAllister, Jochen Prehn, Jamie Young, Jess Bateson, Lewis Gallagher, Magali Michaut, Vivek Iyer, Aikaterini Chatzipli, Syd Barthorpe, Daniel Ciznadija, Ido Sloma, Amy Wesa, David A Tice, Lodewyk Wessels, Mathew Garnett, Daniel B Longley, Ultan McDermott, Simon S McDade
Author Information
  1. Vera Grinkevitch: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  2. Mark Wappett: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom.
  3. Nyree Crawford: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom. ORCID
  4. Stacey Price: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  5. Andrea Lees: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom. ORCID
  6. Christopher McCann: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom.
  7. Katherine McAllister: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom.
  8. Jochen Prehn: Royal College of Surgeons Ireland, Dublin, Ireland. ORCID
  9. Jamie Young: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. ORCID
  10. Jess Bateson: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. ORCID
  11. Lewis Gallagher: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom. ORCID
  12. Magali Michaut: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. ORCID
  13. Vivek Iyer: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  14. Aikaterini Chatzipli: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  15. Syd Barthorpe: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  16. Daniel Ciznadija: Champions Oncology Inc., Rockville, Maryland.
  17. Ido Sloma: Champions Oncology Inc., Rockville, Maryland.
  18. Amy Wesa: Champions Oncology Inc., Rockville, Maryland. ORCID
  19. David A Tice: Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  20. Lodewyk Wessels: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. ORCID
  21. Mathew Garnett: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  22. Daniel B Longley: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom. ORCID
  23. Ultan McDermott: Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom.
  24. Simon S McDade: Patrick G. Johnston Centre for Cancer Research, Queen's University, Belfast, United Kingdom. ORCID
PMID: 35086954 DOI: 10.1158/1535-7163.MCT-21-0532

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.

References

Mol Cancer Ther. 2018 Jul;17(7):1381-1391 [PMID: 29695633]
Biostatistics. 2003 Apr;4(2):249-64 [PMID: 12925520]
Cell Death Differ. 2020 Aug;27(8):2417-2432 [PMID: 32081986]
EMBO J. 2006 Sep 20;25(18):4338-49 [PMID: 16932741]
Bacteriol Rev. 1956 Dec;20(4):243-58 [PMID: 13403845]
J Biol Chem. 2005 May 13;280(19):19401-9 [PMID: 15760909]
Mol Cell. 2013 Sep 26;51(6):751-65 [PMID: 24074954]
Cancer Inform. 2009 Aug 05;7:199-216 [PMID: 19718451]
Blood. 2020 Feb 27;135(9):597-609 [PMID: 31830245]
Nat Med. 2015 Nov;21(11):1350-6 [PMID: 26457759]
Cell. 2011 Mar 4;144(5):646-74 [PMID: 21376230]
Nature. 2015 Jan 29;517(7536):583-8 [PMID: 25494202]
Breast Cancer Res. 2019 Feb 18;21(1):27 [PMID: 30777098]
FEBS J. 2018 Nov;285(22):4104-4123 [PMID: 29806737]
FEBS J. 2020 Oct;287(19):4246-4260 [PMID: 32096279]
EMBO Rep. 2020 Mar 4;21(3):e49254 [PMID: 32009295]
Nat Biotechnol. 2014 Mar;32(3):267-73 [PMID: 24535568]
Cancer Res. 2007 Jun 15;67(12):5754-62 [PMID: 17575142]
Cell Rep. 2016 Oct 18;17(4):1193-1205 [PMID: 27760321]
J Clin Oncol. 2018 Jul 1;36(19):1973-1980 [PMID: 29715056]
J Exp Clin Cancer Res. 2018 Mar 12;37(1):53 [PMID: 29530056]
Eur J Cancer. 2012 May;48(7):1096-107 [PMID: 22154545]
Genome Biol. 2014;15(12):554 [PMID: 25476604]
Mol Cancer Ther. 2013 Jul;12(7):1235-44 [PMID: 23645592]
Nat Commun. 2017 May 31;8:15107 [PMID: 28561063]
Cells. 2014 May 08;3(2):418-37 [PMID: 24814761]
Cancer Immunol Immunother. 2005 May;54(5):499-505 [PMID: 15614529]
Cell Death Differ. 2020 Sep;27(9):2726-2741 [PMID: 32313199]
Nature. 2011 Mar 3;471(7336):104-9 [PMID: 21368833]
Nat Commun. 2017 Nov 24;8(1):1751 [PMID: 29170499]
Clin Cancer Res. 2020 Jun 15;26(12):2819-2826 [PMID: 31900279]
Mol Carcinog. 2020 Nov;59(11):1256-1268 [PMID: 32885857]
Cancer Discov. 2012 Mar;2(3):214-26 [PMID: 22585993]
Cell. 2017 Jul 27;170(3):564-576.e16 [PMID: 28753430]
FEBS J. 2021 Sep;288(18):5374-5388 [PMID: 33660894]
BMC Genomics. 2016 Jan 19;17:65 [PMID: 26781748]
Nat Rev Cancer. 2017 May 24;17(6):352-366 [PMID: 28536452]
Stat Appl Genet Mol Biol. 2004;3:Article3 [PMID: 16646809]
Blood. 2002 Mar 15;99(6):2162-71 [PMID: 11877293]
Sci Rep. 2018 Dec 14;8(1):17862 [PMID: 30552344]
Cell. 2016 Jul 28;166(3):740-754 [PMID: 27397505]

Grants

  1. 24387/Cancer Research UK
  2. 110371/Z/15/Z/Wellcome Trust
  3. MC_PC_17117/Medical Research Council
  4. MR/S021205/1/Medical Research Council
  5. G0400302/Medical Research Council
  6. BB/T002824/1/Biotechnology and Biological Sciences Research Council
  7. 319661/European Research Council
  8. C11884/Cancer Research UK

MeSH Term

Apoptosis
CASP8 and FADD-Like Apoptosis Regulating Protein
Caspase 8
Cell Line, Tumor
Genomics
Humans
Proto-Oncogene Proteins c-bcl-2
TNF-Related Apoptosis-Inducing Ligand

Chemicals

CASP8 and FADD-Like Apoptosis Regulating Protein
Proto-Oncogene Proteins c-bcl-2
TNF-Related Apoptosis-Inducing Ligand
Caspase 8
Journal Article Research Support, Non-U.S. Gov't

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