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Cited by 155DNA and Nucleic Acid ChemistryPARP inhibition in cancer therapyCancer therapeutics and mechanisms

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies

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Hilton, John, Gelmon, Karen, Bedard, Philippe L., Tu, Dongsheng, Xu, Hong, Tinker, Anna V., Goodwin, Rachel, Laurie, Scott A. +24 more·2022·Nature Communications
DOI 10.1038/s41467-022-31199-2PMC PMC9232501
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Abstract

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50–650 mg/m 2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m 2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

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  • A Phase 1 clinical trial of the G4-stabilizing ligand CX-5461 in patients with advanced solid tumors demonstrated a 14% partial response rate in patients deficient in homologous recombination (HR).

    “Notably, a Phase 1 clinical trial of the G4-stabilizing ligand CX-5461 (91), administered to patients with advanced solid tumors, demonstrated a 14% partial response rate in patients deficient in homologous recombination (HR), a critical DNA repair pathway”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [91]

    The Results (Efficacy) report a 14% partial-response rate (4/29) among patients with breast, ovarian, or pancreatic tumors—tumor types in which HR-gene alterations can have a functional role. That is not a rate specifically measured in patients confirmed to be HR-deficient: three responders had pathogenic BRCA1/2 or PALB2 alterations, while the fourth had a TP53 mutation and a BRCA2 variant of uncertain significance. (LLM, conf=0.91)

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References 31 · Cited by 155

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  1. [1]Bryan TM Baumann P G-Quadruplexes: from guanine gels to chemotherapeutics [Internet] Mol. Biotechnol. 2011 49 198 208 10.1007/s12033-011-9395-5 21416200 PMC3172417 · DOI
  2. [2]Ohnmacht SA Discovery of new G-quadruplex binding chemotypes Chem. Commun. 2014 50 960 963 10.1039/C3CC48616H PMC3901018 24302123 · DOI
  3. [3]Xu H CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours Nat. Commun. 2017 8 14432 10.1038/ncomms14432 28211448 PMC5321743 · DOI
  4. [4]Tarsounas M Tijsterman M Genomes and G-quadruplexes: for better or for worse J. Mol. Biol. 2013 425 4782 4789 10.1016/j.jmb.2013.09.026 24076189 · DOI
  5. [5]Lopes J G-quadruplex-induced instability during leading-strand replication: G-quadruplex-induced instability EMBO J. 2011 30 4033 4046 10.1038/emboj.2011.316 21873979 PMC3209785 · DOI
  6. [6]Neidle S Quadruplex nucleic acids as novel therapeutic targets J. Med Chem. 2016 59 5987 6011 10.1021/acs.jmedchem.5b01835 26840940 · DOI
  7. [7]McLuckie KIE G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells J. Am. Chem. Soc. 2013 135 9640 9643 10.1021/ja404868t 23782415 PMC3964824 · DOI
  8. [8]Chartron E Theillet C Guiu S Jacot W Targeting homologous repair deficiency in breast and ovarian cancers: biological pathways, preclinical and clinical data Crit. Rev. Oncol. Hematol. 2019 133 58 73 10.1016/j.critrevonc.2018.10.012 30661659 · DOI
  9. [9]Domchek SM Evolution of genetic testing for inherited susceptibility to breast cancer J. Clin. Oncol. 2015 33 295 296 10.1200/JCO.2014.59.3178 25512463 · DOI
  10. [10]Yap TA Plummer R Azad NS Helleday T The DNA damaging revolution: PARP inhibitors and beyond Am. Soc. Clin. Oncol. Educ. Book 2019 39 185 195 10.1200/EDBK_238473 31099635 · DOI
  11. [11]Tutt A Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial Nat. Med. 2018 24 628 637 10.1038/s41591-018-0009-7 29713086 PMC6372067 · DOI
  12. [12]Drygin D O’Brien SE Hannan RD McArthur GA Von Hoff DD Targeting the nucleolus for cancer-specific activation of p53 Drug Discov. Today 2014 19 259 265 10.1016/j.drudis.2013.08.012 23993916 · DOI
  13. [13]Khot A First-in-hman RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: results of a phase i dose-escalation study Cancer Discov. 2019 9 1036 1049 10.1158/2159-8290.CD-18-1455 31092402 · DOI
  14. [14]Edwards SL Resistance to therapy caused by intragenic deletion in BRCA2 Nature 2008 451 1111 1115 10.1038/nature06548 18264088 · DOI · Paper page
  15. [15]de Guidi G Bracchitta G Catalfo A Photosensitization reactions of fluoroquinolones and their biological consequences Photochem. Photobiol. 2011 87 1214 1229 10.1111/j.1751-1097.2011.00978.x 21770950 · DOI
  16. [16]Jonsson P Tumour lineage shapes BRCA-mediated phenotypes [Internet] Nature 2019 571 576 579 10.1038/s41586-019-1382-1 31292550 PMC7048239 · DOI
  17. [17]Bouwman P Jonkers J Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin. Cancer Res. 2014 20 540 547 10.1158/1078-0432.CCR-13-0225 24270682 · DOI
  18. [18]Masud T. et al. Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461. Sci. Rep. 11, 9812 (2021). PMC8105411 33963218
  19. [20]Pan M The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma Nat Commun 2021 12 6468 10.1038/s41467-021-26640-x 34753908 PMC8578635 · DOI
  20. [21]Olivieri M A genetic map of the response to DNA damage in human cells Cell 2020 182 481 96.e21 10.1016/j.cell.2020.05.040 32649862 PMC7384976 · DOI · Paper page
  21. [22]Bruno PM The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning Proc. Natl. Acad. Sci. USA 2020 117 4053 4060 10.1073/pnas.1921649117 32041867 PMC7049172 · DOI · Paper page
  22. [23]Eisenhauer EA Verweij J 11 New response evaluation criteria in solid tumors: RECIST GUIDELINE VERSION 1.1 [Internet] Eur. J. Cancer Suppl. 2009 7 5 10.1016/S1359-6349(09)70018-7 19097774 · DOI
  23. [24]Haile S Automated high throughput nucleic acid purification from formalin-fixed paraffin-embedded tissue samples for next generation sequence analysis PLoS ONE 2017 12 e0178706 10.1371/journal.pone.0178706 28570594 PMC5453589 · DOI
  24. [25]Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM [Internet]. arXiv Available from: http://arxiv.org/abs/1303.3997 (2013). · arXiv
  25. [26]Kim S Strelka2: fast and accurate calling of germline and somatic variants Nat. Methods 2018 15 591 594 10.1038/s41592-018-0051-x 30013048 · DOI
  26. [27]Ding J Feature-based classifiers for somatic mutation detection in tumour–normal paired sequencing data Bioinformatics 2011 28 167 175 10.1093/bioinformatics/btr629 22084253 PMC3259434 · DOI
  27. [28]Frankish A GENCODE reference annotation for the human and mouse genomes [Internet] Nucleic Acids Res. 2019 47 D766 D773 10.1093/nar/gky955 30357393 PMC6323946 · DOI
  28. [30]Tate JG COSMIC: the catalogue of somatic mutations in cancer [Internet] Nucleic Acids Res. 2019 47 D941 D947 10.1093/nar/gky1015 30371878 PMC6323903 · DOI · Paper page
  29. [31]Cingolani P A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 Fly 2012 6 80 92 10.4161/fly.19695 22728672 PMC3679285 · DOI · Paper page

Authors
Hilton, J., Gelmon, K., Bedard, P. L., Tu, D., Xu, H., Tinker, A. V., Goodwin, R., Laurie, S. A., Jonker, D., Hansen, A. R., Veitch, Z. W., Renouf, D. J., Hagerman, L., Lui, H., Chen, B., Kellar, D., Li, I., Lee, S.-E., Kono, T., Cheng, B. Y. C., Yap, D., Lai, D., Beatty, S., Soong, J., Pritchard, K. I., Soria-Bretones, I., Chen, E., Feilotter, H., Rushton, M., Seymour, L., Aparicio, S., & Cescon, D. W.
Affiliations
  • Ottawa Hospital Research Institute (CA)
  • BC Cancer Agency (CA)
  • University Health Network (CA)
  • Canadian Cancer Trials Group (CA)
  • Sunnybrook Health Science Centre (CA)
Corresponding author
Seymour, Lesley
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-06-24
Volume
13
Issue
1
Pages
3607-3607
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-31199-2
PMC
PMC9232501
OpenAlex
W4283363468
Cited by
155
References
31
Citations by year
2026: 41 · 2025: 41 · 2024: 36 · 2023: 24 · 2022: 13
FWCI
9.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • American Association for Cancer Research
  • Breast Cancer Research Foundation (BCRF-20-180)
  • Ontario Institute for Cancer Research
  • Government of Ontario (SU2C-AACR-DT-18-15)
  • Terry Fox Research Institute
  • Stand Up To Cancer (80550 6730 RR0001, SU2C-AACR-DT-18-15)
  • Canadian Institutes of Health Research (148429_1, 40044)
  • Canadian Cancer Society Research Institute (705636, 704970, 705617)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
Keywords
CX-5461, G-quadruplex stabilizers, synthetic lethality, homologous recombination deficiency, DNA repair deficiency, advanced solid tumors, recommended phase 2 dose, phototoxicity, pharmacokinetics, predictive biomarkers
MeSH terms
DNA, Humans, Naphthyridines, Neoplasms, Benzothiazoles

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