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2000
Volume 32, Issue 34
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
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Abstract

The extracellular matrix (ECM) plays a pivotal role in maintaining tissue architecture and regulating cellular behavior. Recent insights have highlighted Discoidin Domain Receptors (DDRs) as critical mediators in cancer progression and therapeutic resistance. This editorial synthesizes the current understanding of DDR1 and DDR2, unique members of the receptor tyrosine kinase family activated by collagen, focusing on their distinct roles in cell-ECM interactions and cancer biology. We explore emerging therapeutic strategies targeting DDRs, with particular emphasis on differential approaches to DDR1 and DDR2 degradation. Additionally, we examine the complex relationship between DDR inhibition, degradation, and knockout phenotypes, presenting the novel DDR1 degrader LLC355 as a case study. By integrating findings from recent molecular investigations and clinical studies, we propose a comprehensive framework for DDR-targeted therapies in cancer treatment, highlighting their potential to overcome immune evasion mechanisms and enhance the efficacy of existing therapies.

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2025-02-11
2025-10-31

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References

  1. JalanA.A. SammonD. HartgerinkJ.D. BrearP. StottK. HamaiaS.W. HunterE.J. WalkerD.R. LeitingerB. FarndaleR.W. Chain alignment of collagen I deciphered using computationally designed heterotrimers.Nat. Chem. Biol.202016442342910.1038/s41589‑019‑0435‑y31907373
     [Google Scholar]
  2. Di MartinoJ.S. NobreA.R. MondalC. TahaI. FariasE.F. FertigE.J. NabaA. Aguirre-GhisoJ.A. Bravo-CorderoJ.J. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.Nat. Can.2021319010710.1038/s43018‑021‑00291‑935121989
     [Google Scholar]
  3. AmbrogioC. Gómez-LópezG. FalconeM. VidalA. NadalE. CrosettoN. BlascoR.B. Fernández-MarcosP.J. Sánchez-CéspedesM. RenX. WangZ. DingK. HidalgoM. SerranoM. VillanuevaA. SantamaríaD. BarbacidM. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.Nat. Med.201622327027710.1038/nm.404126855149
     [Google Scholar]
  4. LeitingerB. HohenesterE. Mammalian collagen receptors.Matrix Biol.200726314615510.1016/j.matbio.2006.10.00717141492
     [Google Scholar]
  5. CoelhoN.M. AroraP.D. van PuttenS. BooS. PetrovicP. LinA.X. HinzB. McCullochC.A. Discoidin domain receptor 1 mediates myosin-dependent collagen contraction.Cell Rep.20171871774179010.1016/j.celrep.2017.01.06128199848
     [Google Scholar]
  6. LiuJ. ZhaoC. XiaoX. LiA. LiuY. ZhaoJ. FanL. LiangZ. PangW. YaoW. LiW. ZhouJ. Endothelial discoidin domain receptor 1 senses flow to modulate YAP activation.Nat. Commun.2023141645710.1038/s41467‑023‑42341‑z37833282
     [Google Scholar]
  7. SunX. WuB. ChiangH.C. DengH. ZhangX. XiongW. LiuJ. RozeboomA.M. HarrisB.T. BlommaertE. GomezA. GarciaR.E. ZhouY. MitraP. PrevostM. ZhangD. BanikD. IsaacsC. BerryD. LaiC. ChaldekasK. LathamP.S. BrantnerC.A. PopratiloffA. JinV.X. ZhangN. HuY. PujanaM.A. CurielT.J. AnZ. LiR. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.Nature2021599788667367810.1038/s41586‑021‑04057‑234732895
     [Google Scholar]
  8. LeitingerB. Discoidin domain receptor functions in physiological and pathological conditions.Int. Rev. Cell Mol. Biol.2014310398710.1016/B978‑0‑12‑800180‑6.00002‑524725424
     [Google Scholar]
  9. TakaiK. DrainA.P. LawsonD.A. LittlepageL.E. KarpujM. KessenbrockK. LeA. InoueK. WeaverV.M. WerbZ. Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers.Genes Dev.2018323-424425710.1101/gad.301366.11729483153
     [Google Scholar]
  10. ZhongX. ZhangW. SunT. DDR1 promotes breast tumor growth by suppressing antitumor immunity.Oncol. Rep.20194262844285410.3892/or.2019.733831578591
     [Google Scholar]
  11. RizzoA. MollicaV. MassariF. Expression of programmed cell death ligand 1 as a predictive biomarker in metastatic urothelial carcinoma patients treated with first-line immune checkpoint inhibitors versus chemotherapy: A systematic review and meta-analysis.Eur. Urol. Focus20228115215910.1016/j.euf.2021.01.00333516645
     [Google Scholar]
  12. BerestjukI. LecacheurM. CarminatiA. DiazziS. RoveraC. Prod’hommeV. OhannaM. PopovicA. MallavialleA. LarbretF. PisanoS. AudebertS. PasseronT. GaggioliC. GirardC.A. DeckertM. Tartare-DeckertS. Targeting discoidin domain receptors DDR1 and DDR2 overcomes matrix‐mediated tumor cell adaptation and tolerance to BRAF‐targeted therapy in melanoma.EMBO Mol. Med.2022142e1181410.15252/emmm.20191181434957688
     [Google Scholar]
  13. BantscheffM. EberhardD. AbrahamY. BastuckS. BoescheM. HobsonS. MathiesonT. PerrinJ. RaidaM. RauC. ReaderV. SweetmanG. BauerA. BouwmeesterT. HopfC. KruseU. NeubauerG. RamsdenN. RickJ. KusterB. DrewesG. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors.Nat. Biotechnol.20072591035104410.1038/nbt132817721511
     [Google Scholar]
  14. RixU. HantschelO. DürnbergerG. Remsing RixL.L. PlanyavskyM. FernbachN.V. KaupeI. BennettK.L. ValentP. ColingeJ. KöcherT. Superti-FurgaG. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.Blood2007110124055406310.1182/blood‑2007‑07‑10206117720881
     [Google Scholar]
  15. KimH.G. TanL. WeisbergE.L. LiuF. CanningP. ChoiH.G. EzellS.A. WuH. ZhaoZ. WangJ. MandinovaA. GriffinJ.D. BullockA.N. LiuQ. LeeS.W. GrayN.S. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor.ACS Chem. Biol.20138102145215010.1021/cb400430t23899692
     [Google Scholar]
  16. LiuJ. ChiangH.C. XiongW. LaurentV. GriffithsS.C. DülferJ. DengH. SunX. YinY.W. LiW. AudolyL.P. AnZ. SchürpfT. LiR. ZhangN. A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer.J. Immunother. Cancer2023116e00672010.1136/jitc‑2023‑00672037328286
     [Google Scholar]
  17. LiuL. ZhaoL. YangL. ChaiM. LiuZ. MaN. WangY. WuQ. GuoJ. ZhouF. HuangW. RenX. WangJ. DingM. WangZ. DingK. Discovery of LLC355 as an Autophagy-tethering compound for the degradation of discoidin domain receptor 1.J. Med. Chem.202467108043805910.1021/acs.jmedchem.4c0016238730324
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673365845250131104153
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Extracellular Matrix Modulation via DDR Kinase Degradation: Exploring New Therapeutic Frontiers
Curr. Med. Chem. 32, 7560 (2025); https://doi.org/10.2174/0109298673365845250131104153
/content/journals/cmc/10.2174/0109298673365845250131104153
/content/journals/cmc/10.2174/0109298673365845250131104153
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  • Article Type:     Editorial
Keyword(s): cancer therapy; DDR1; DDR2; degradation; extracellular matrix; immune evasion; LLC355; receptor tyrosine kinases

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