Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.

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  • Additional Information
    • Source:
      Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: Electronic Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: MEDLINE
    • Publication Information:
      Original Publication: Albany, N.Y. : Impact Journals
    • Subject Terms:
      Trifluridine*/pharmacology ; Phenylurea Compounds*/pharmacology ; Pyridines*/pharmacology ; Drug Synergism* ; Proto-Oncogene Proteins B-raf*/genetics ; Proto-Oncogene Proteins B-raf*/metabolism ; Proto-Oncogene Proteins p21(ras)*/genetics ; Proto-Oncogene Proteins p21(ras)*/metabolism ; Neovascularization, Pathologic*/drug therapy ; Neovascularization, Pathologic*/genetics ; Neovascularization, Pathologic*/metabolism ; Xenograft Model Antitumor Assays* ; Neoplastic Stem Cells*/drug effects ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; Gastrointestinal Neoplasms*/drug therapy ; Gastrointestinal Neoplasms*/genetics ; Gastrointestinal Neoplasms*/pathology ; Gastrointestinal Neoplasms*/metabolism ; Uracil*/pharmacology ; Uracil*/analogs & derivatives ; STAT3 Transcription Factor*/metabolism ; STAT3 Transcription Factor*/genetics ; Thymine*/pharmacology ; Drug Combinations* ; Pyrrolidines*/pharmacology ; Pyrrolidines*/therapeutic use ; Mutation*; Humans ; Animals ; Mice ; Cell Line, Tumor ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; MAP Kinase Signaling System/drug effects ; Signal Transduction/drug effects ; Cell Proliferation/drug effects ; Angiogenesis
    • Abstract:
      Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo . TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo . TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.
    • References:
      Oncologist. 2020 Jan;25(1):e75-e84. (PMID: 31591140)
      Nat Rev Cancer. 2018 Nov;18(11):669-680. (PMID: 30228301)
      Cell Death Dis. 2021 Nov 16;12(12):1084. (PMID: 34785656)
      Lancet Oncol. 2016 Aug;17(8):e323. (PMID: 27375105)
      Semin Cancer Biol. 2018 Dec;53:139-155. (PMID: 30081228)
      Semin Cancer Biol. 2019 Jun;56:87-99. (PMID: 29128510)
      Lab Invest. 1995 Dec;73(6):844-50. (PMID: 8558846)
      Oncogene. 2019 Mar;38(11):1920-1935. (PMID: 30390074)
      Lancet Oncol. 2017 Sep;18(9):1172-1181. (PMID: 28760399)
      Eur J Cancer. 2019 Mar;109:70-83. (PMID: 30690295)
      J Exp Clin Cancer Res. 2018 Jul 13;37(1):151. (PMID: 30005681)
      J Hematol Oncol. 2017 Oct 6;10(1):162. (PMID: 28985760)
      Cancer Immunol Res. 2017 Sep;5(9):790-803. (PMID: 28775208)
      J Exp Clin Cancer Res. 2019 Apr 25;38(1):173. (PMID: 31023337)
      Br J Cancer. 2016 Jun 14;114(12):1334-42. (PMID: 27195424)
      J Clin Oncol. 2018 Feb 1;36(4):350-358. (PMID: 29215955)
      Cancer Discov. 2022 Apr 1;12(4):1002-1021. (PMID: 35078784)
      Mol Cancer Ther. 2016 May;15(5):890-8. (PMID: 26921392)
      Cancer Res. 2020 Feb 15;80(4):890-900. (PMID: 31857293)
      J Hepatol. 2018 Oct;69(4):826-839. (PMID: 29885413)
      Mol Cancer Ther. 2015 Apr;14(4):1004-13. (PMID: 25700705)
      Cancer Sci. 2016 May;107(5):601-8. (PMID: 26865419)
      Am J Cancer Res. 2017 Oct 01;7(10):2032-2040. (PMID: 29119052)
      Lancet Oncol. 2018 Nov;19(11):1437-1448. (PMID: 30355453)
      Cancer Res. 2006 Dec 15;66(24):11851-8. (PMID: 17178882)
      Cell Death Dis. 2020 May 7;11(5):339. (PMID: 32382022)
      Sci Rep. 2019 Oct 16;9(1):14861. (PMID: 31619711)
      Pharmacol Res. 2018 Nov;137:193-204. (PMID: 30316903)
      Cell Cycle. 2017 Jun 18;16(12):1193-1200. (PMID: 28486050)
      Clin Cancer Res. 2014 Nov 15;20(22):5768-76. (PMID: 25248379)
      Mol Oncol. 2017 Aug;11(8):1065-1077. (PMID: 28486761)
      Clin Cancer Res. 2016 Jun 15;22(12):2835-9. (PMID: 27126991)
      Lancet Oncol. 2015 Jun;16(6):619-29. (PMID: 25981818)
      Oxid Med Cell Longev. 2018 Jan 31;2018:3537471. (PMID: 29636841)
      Int J Biol Sci. 2022 Jan 1;18(3):942-955. (PMID: 35173528)
      Lancet. 2017 Jan 7;389(10064):56-66. (PMID: 27932229)
      J Cell Physiol. 2019 Apr;234(4):4445-4453. (PMID: 30191978)
      Cancer Lett. 2017 Feb 1;386:100-109. (PMID: 27864115)
      JAMA Oncol. 2020 Jan 01;6(1):e193531. (PMID: 31600365)
      Redox Biol. 2021 Nov;47:102144. (PMID: 34562873)
      Cancer Res. 2015 Oct 1;75(19):4003-11. (PMID: 26292361)
      Cancer Res. 2010 Jan 15;70(2):440-6. (PMID: 20068163)
      Stem Cell Rev Rep. 2016 Aug;12(4):492-9. (PMID: 27207017)
      Eur J Cancer. 2017 Nov;86:197-206. (PMID: 28992563)
      Angiogenesis. 2009;12(3):267-74. (PMID: 19399631)
      Ann Oncol. 2018 Apr 1;29(4):835-856. (PMID: 29452346)
      Oncol Rep. 2016 Dec;36(6):3123-3130. (PMID: 27805254)
      Cancer Biol Ther. 2015;16(12):1710-9. (PMID: 26561209)
      Ann Oncol. 2017 May 1;28(5):1015-1022. (PMID: 28453695)
      J Exp Clin Cancer Res. 2018 Dec 12;37(1):311. (PMID: 30541574)
      N Engl J Med. 2015 May 14;372(20):1909-19. (PMID: 25970050)
    • Contributed Indexing:
      Keywords: ERK1/2; TAS102; angiogenesis; microvessel density; regorafenib
    • Accession Number:
      24T2A1DOYB (regorafenib)
      RMW9V5RW38 (Trifluridine)
      0 (Phenylurea Compounds)
      0 (Pyridines)
      EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
      EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
      0 (trifluridine tipiracil drug combination)
      56HH86ZVCT (Uracil)
      EC 2.7.11.1 (BRAF protein, human)
      0 (STAT3 Transcription Factor)
      QR26YLT7LT (Thymine)
      0 (Drug Combinations)
      0 (KRAS protein, human)
      0 (Pyrrolidines)
      0 (STAT3 protein, human)
    • Publication Date:
      Date Created: 20240702 Date Completed: 20240702 Latest Revision: 20240704
    • Publication Date:
      20240704
    • Accession Number:
      PMC11218792
    • Accession Number:
      10.18632/oncotarget.28602
    • Accession Number:
      38953895