Co-treatment with vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, suppresses radiotherapy-induced epithelial-to-mesenchymal transition, cancer cell stemness, and lung metastasis of breast cancer

1Ko YS, Jin H, Lee JS, Park SW, Chang KC, Kang KM, et al. Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells. Oncol Rep 2018; 40: 3752-62. doi: 10.3892/or.2018.6714Ko YS Jin H Lee JS Park SW Chang KC Kang KM et al Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells Oncol Rep 2018 40 3752 62 10.3892/or.2018.671430272295Open DOISearch in Google Scholar

2Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011; 11: 239-53. doi: 10.1038/nrc3007Begg AC Stewart FA Vens C Strategies to improve radiotherapy with targeted drugs Nat Rev Cancer 2011 11 239 53 10.1038/nrc300721430696Open DOISearch in Google Scholar

3Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 2015; 15: 409-25. doi: 10.1038/nrc3958Barker HE Paget JT Khan AA Harrington KJ The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence Nat Rev Cancer 2015 15 409 25 10.1038/nrc3958489638926105538Open DOISearch in Google Scholar

4Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Eleojo Musa A, et al. TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury. Pharmacol Res 2020; 155: 104745. doi: 10.1016/j.phrs.2020.104745Farhood B Khodamoradi E Hoseini-Ghahfarokhi M Motevaseli E Mirtavoos-Mahyari H Eleojo Musa A et al TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury Pharmacol Res 2020 155 104745 10.1016/j.phrs.2020.10474532145401Open DOISearch in Google Scholar

5Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108. doi: 10.3322/caac.21262Torre LA Bray F Siegel RL Ferlay J Lortet-Tieulent J Jemal A Global cancer statistics, 2012 CA Cancer J Clin 2015 65 87 108 10.3322/caac.2126225651787Open DOISearch in Google Scholar

6Lee SY, Jeong EK, Ju MK, Jeon HM, Kim MY, Kim CH, et al. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer 2017; 16: 10. doi: 10.1186/s12943-016-0577-4Lee SY Jeong EK Ju MK Jeon HM Kim MY Kim CH et al Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation Mol Cancer 2017 16 10 10.1186/s12943-016-0577-4528272428137309Open DOISearch in Google Scholar

7Dancea HC, Shareef MM, Ahmed MM. Role of radiation-induced TGF-beta signaling in cancer therapy. Mol Cell Pharmacol 2009; 1: 44-56. doi: 10.4255/mcpharmacol.09.06Dancea HC Shareef MM Ahmed MM Role of radiation-induced TGF-beta signaling in cancer therapy Mol Cell Pharmacol 2009 1 44 56 10.4255/mcpharmacol.09.06284464020336170Open DOISearch in Google Scholar

8Hong E, Park S, Ooshima A, Hong CP, Park J, Heo JS, et al. Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Sci Rep 2020; 10: 2935. doi: 10.1038/s41598-020-59893-5Hong E Park S Ooshima A Hong CP Park J Heo JS et al Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models Sci Rep 2020 10 2935 10.1038/s41598-020-59893-5703124232076068Open DOISearch in Google Scholar

9Park SY, Kim MJ, Park SA, Kim JS, Min KN, Kim DK, et al. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget 2015; 6: 37526-43. doi: 10.18632/oncotarget.6063Park SY Kim MJ Park SA Kim JS Min KN Kim DK et al Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells Oncotarget 2015 6 37526 43 10.18632/oncotarget.6063474194626462028Open DOISearch in Google Scholar

10Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741-51. doi: 10.1038/onc.2010.215Singh A Settleman J EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer Oncogene 2010 29 4741 51 10.1038/onc.2010.215317671820531305Open DOISearch in Google Scholar

11Diepenbruck M, Christofori G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 2016; 43: 7-13. doi: 10.1016/j.ceb.2016.06.002Diepenbruck M Christofori G Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 2016 43 7 13 10.1016/j.ceb.2016.06.00227371787Open DOISearch in Google Scholar

12Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol 2019; 29: 212-26. doi: 10.1016/j. tcb.2018.12.001Pastushenko I Blanpain C EMT transition states during tumor progression and metastasis Trends Cell Biol 2019 29 212 26 10.1016/j.tcb.2018.12.00130594349Open DOISearch in Google Scholar

13Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K, et al. Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene 2011; 30: 1470-80. doi: 10.1038/onc.2010.531Wang Y Yu Y Tsuyada A Ren X Wu X Stubblefield K et al Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM Oncogene 2011 30 1470 80 10.1038/onc.2010.531306385621102523Open DOISearch in Google Scholar

14Fuxe J, Vincent T, Garcia de Herreros A. Transcriptional crosstalk between TGF-β and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 2010; 9: 2363-74. doi: 10.4161/cc.9.12.12050Fuxe J Vincent T Garcia de Herreros A Transcriptional crosstalk between TGF-β and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes Cell Cycle 2010 9 2363 74 10.4161/cc.9.12.1205020519943Open DOISearch in Google Scholar

15Keedy VL, Bauer TM, Clarke JM, Hurwitz H, Baek I, Ha I, et al. Association of TGF-β responsive signature with anti-tumor effect of vactosertib, a potent, oral TGF-β receptor type I (TGFBRI) inhibitor in patients with advanced solid tumors. [abstract]. J Clin Oncol 2018; 36(15 Suppl): 3031. doi: 10.1200/ JCO.2018.36.15_SUPPL.3031Keedy VL Bauer TM Clarke JM Hurwitz H Baek I Ha I et al Association of TGF-β responsive signature with anti-tumor effect of vactosertib, a potent, oral TGF-β receptor type I (TGFBRI) inhibitor in patients with advanced solid tumors [abstract]. J Clin Oncol 2018 36 15 Suppl 3031 10.1200/JCO.2018.36.15_SUPPL.3031Open DOISearch in Google Scholar

16Jung SY, Hwang S, Clarke JM, Bauer TM, Keedy VL, Lee H, et al. Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study. Invest New Drugs 2020; 38: 812-20. doi: 10.1007/s10637-019-00835-yJung SY Hwang S Clarke JM Bauer TM Keedy VL Lee H et al Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study Invest New Drugs 2020 38 812 20 10.1007/s10637-019-00835-y31300967Open DOISearch in Google Scholar

17Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, et al. Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J Med Chem 2014; 57: 421338. doi: 10.1021/jm500115wJin CH Krishnaiah M Sreenu D Subrahmanyam VB Rao KS Lee HJ et al Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent J Med Chem 2014 57 421338 10.1021/jm500115w24786585Open DOISearch in Google Scholar

18Son JY, Park SY, Kim SJ, Lee SJ, Park SA, Kim MJ, et al. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther 2014; 13: 1704-16. doi: 10.1158/1535-7163.MCT-13-0903Son JY Park SY Kim SJ Lee SJ Park SA Kim MJ et al EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis Mol Cancer Ther 2014 13 1704 16 10.1158/1535-7163.MCT-13-090324817629Open DOISearch in Google Scholar

19Park SA, Kim MJ, Park SY, Kim JS, Lee SJ, Woo HA, et al. EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cell Mol Life Sci 2015; 72: 2023-39. doi: 10.1007/s00018-014-1798-6Park SA Kim MJ Park SY Kim JS Lee SJ Woo HA et al EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling Cell Mol Life Sci 2015 72 2023 39 10.1007/s00018-014-1798-625487606Open DOISearch in Google Scholar

20Yoon JH, Jung SM, Park SH, Kato M, Yamashita T, Lee IK, et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol Med 2013; 5: 1720-39. doi: 10.1002/ emmm.201302524Yoon JH Jung SM Park SH Kato M Yamashita T Lee IK et al Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes EMBO Mol Med 2013 5 1720 39 10.1002/emmm.201302524384048824127404Open DOISearch in Google Scholar

21Park S, Yang KM, Park Y, Hong E, Hong CP, Park J, et al. Identification of epithelial-mesenchymal transition-related target genes induced by the mutation of Smad3 linker phosphorylation. J Cancer Prev 2018; 23: 1-9. doi: 10.15430/JCP.2018.23.1.1Park S Yang KM Park Y Hong E Hong CP Park J et al Identification of epithelial-mesenchymal transition-related target genes induced by the mutation of Smad3 linker phosphorylation J Cancer Prev 2018 23 1 9 10.15430/JCP.2018.23.1.1588648929629343Open DOISearch in Google Scholar

22Jung SY, Yug JS, Clarke JM, Bauer TM, Keedy VL, Hwang S, et al. Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol 2020; 85: 173-83. doi: 10.1007/s00280-019-03979-zJung SY Yug JS Clarke JM Bauer TM Keedy VL Hwang S et al Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors Cancer Chemother Pharmacol 2020 85 173 83 10.1007/s00280-019-03979-z31673825Open DOISearch in Google Scholar

23Servant N, Bollet MA, Halfwerk H, Bleakley K, Kreike B, Jacob L, et al. Search for a gene expression signature of breast cancer local recurrence in young women. Clin Cancer Res 2012; 18: 1704-15. doi: 10.1158/1078-0432.CCR-11-1954Servant N Bollet MA Halfwerk H Bleakley K Kreike B Jacob L et al Search for a gene expression signature of breast cancer local recurrence in young women Clin Cancer Res 2012 18 1704 15 10.1158/1078-0432.CCR-11-195422271875Open DOISearch in Google Scholar

24Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol Ther 2018; 19: 858-68. doi: 10.1080/15384047.2018.1456599Jin L Han B Siegel E Cui Y Giuliano A Cui X Breast cancer lung metastasis: Molecular biology and therapeutic implications Cancer Biol Ther 2018 19 858 68 10.1080/15384047.2018.1456599630034129580128Open DOISearch in Google Scholar

25Samarakoon R, Overstreet JM, Higgins PJ. TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal 2013; 25: 264-8. doi: 10.1016/j.cellsig.2012.10.003Samarakoon R Overstreet JM Higgins PJ TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities Cell Signal 2013 25 264 8 10.1016/j.cellsig.2012.10.003350826323063463Open DOISearch in Google Scholar

26Breitzig M, Bhimineni C, Lockey R, Kolliputi N. 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol 2016; 311: C537-C543. doi: 10.1152/ajpcell.00101.2016Breitzig M Bhimineni C Lockey R Kolliputi N 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol 2016 311 C537 C543 10.1152/ajpcell.00101.2016512975027385721Open DOISearch in Google Scholar

27Langlands FE, Horgan K, Dodwell DD, Smith L. Breast cancer subtypes: response to radiotherapy and potential radiosensitisation. Br J Radiol 2013; 86: 20120601. doi: 10.1259/bjr.20120601Langlands FE Horgan K Dodwell DD Smith L Breast cancer subtypes: response to radiotherapy and potential radiosensitisation Br J Radiol 2013 86 20120601 10.1259/bjr.20120601360805523392193Open DOISearch in Google Scholar

28Tripathy J, Chowdhury AR, Prusty M, Muduli K, Priyadarshini N, Reddy KS, et al. α-Lipoic acid prevents the ionizing radiation-induced epithelial-mesenchymal transition and enhances the radiosensitivity in breast cancer cells. Eur J Pharmacol 2020; 871: 172938. doi: 10.1016/j.ejphar.2020.172938Tripathy J Chowdhury AR Prusty M Muduli K Priyadarshini N Reddy KS et al α-Lipoic acid prevents the ionizing radiation-induced epithelial-mesenchymal transition and enhances the radiosensitivity in breast cancer cells Eur J Pharmacol 2020 871 172938 10.1016/j.ejphar.2020.17293831958458Open DOISearch in Google Scholar

29Hou J, Li L, Zhu H, Chen H, Wei N, Dai M, et al. Association between breast cancer cell migration and radiosensitivity in vitro Oncol Lett 2019; 18: 687784. doi: 10.3892/ol.2019.11027Hou J Li L Zhu H Chen H Wei N Dai M et al Association between breast cancer cell migration and radiosensitivity in vitro Oncol Lett 2019 18 687784 10.3892/ol.2019.11027687631831807191Open DOISearch in Google Scholar

30Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells 2012; 30: 833-44. doi: 10.1002/stem.1058Lagadec C Vlashi E Della Donna L Dekmezian C Pajonk F Radiation-induced reprogramming of breast cancer cells Stem Cells 2012 30 833 44 10.1002/stem.1058341333322489015Open DOISearch in Google Scholar

31Sundahl N, Duprez F, Ost P, De Neve W, Mareel M. Effects of radiation on the metastatic process. Mol Med 2018; 24: 16. doi: 10.1186/s10020-018-0015-8Sundahl N Duprez F Ost P De Neve W Mareel M Effects of radiation on the metastatic process Mol Med 2018 24 16 10.1186/s10020-018-0015-8601689330134800Open DOISearch in Google Scholar

32Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol 2021; 14: 55. doi: 10.1186/s13045-021-01053-xKim BG Malek E Choi SH Ignatz-Hoover JJ Driscoll JJ Novel therapies emerging in oncology to target the TGF-β pathway J Hematol Oncol 2021 14 55 10.1186/s13045-021-01053-x802255133823905Open DOISearch in Google Scholar

33Kim TW, Lee KW, Ahn JB, Park YS, Ock CY, Park H, et al. Tumor microenvironment based on PD-L1 and CD8 T-cell infiltration correlated with the response of MSS mCRC patients treated vactosertib in combination with pembrolizumab. [abstract]. J Immunother Cancer 2021; 9(Suppl 2): A82. Abstr. No. 74. doi: 10.1136/jitc-2021-SITC2021.074Kim TW Lee KW Ahn JB Park YS Ock CY Park H et al Tumor microenvironment based on PD-L1 and CD8 T-cell infiltration correlated with the response of MSS mCRC patients treated vactosertib in combination with pembrolizumab [abstract]. J Immunother Cancer 2021 9 Suppl 2 A82 Abstr. No. 74 10.1136/jitc-2021-SITC2021.074Open DOISearch in Google Scholar

34Kaowinn S, Kim J, Lee J, Shin DH, Kang CD, Kim DK, et al. Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling. Oncotarget 2017; 8: 5092-110. doi: 10.18632/oncotarget.13867Kaowinn S Kim J Lee J Shin DH Kang CD Kim DK et al Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling Oncotarget 2017 8 5092 110 10.18632/oncotarget.13867535489527974707Open DOISearch in Google Scholar

35Chang HY, Tseng YK, Chen YC, Shu CW, Lin MI, Liou HH, et al. High snail expression predicts a poor prognosis in breast invasive ductal carcinoma patients with HER2/EGFR-positive subtypes. Surg Oncol 2018; 27: 314-20. doi: 10.1016/j.suronc.2018.05.002Chang HY Tseng YK Chen YC Shu CW Lin MI Liou HH et al High snail expression predicts a poor prognosis in breast invasive ductal carcinoma patients with HER2/EGFR-positive subtypes Surg Oncol 2018 27 314 20 10.1016/j.suronc.2018.05.00229937187Open DOISearch in Google Scholar

36Wang Y, Shi J, Chai K, Ying X, Zhou BP. The role of Snail in EMT and tumorigenesis. Curr Cancer Drug Targets 2013; 13: 963-72. doi: 10.2174/15680096113136660102Wang Y Shi J Chai K Ying X Zhou BP The role of Snail in EMT and tumorigenesis Curr Cancer Drug Targets 2013 13 963 72 10.2174/15680096113136660102400476324168186Open DOISearch in Google Scholar

37Yadav P, Shankar BS. Radio resistance in breast cancer cells is mediated through TGF-β signalling, hybrid epithelial-mesenchymal phenotype and cancer stem cells. Biomed Pharmacother 2019; 111: 119-30. doi: 10.1016/j. biopha.2018.12.055Yadav P Shankar BS Radio resistance in breast cancer cells is mediated through TGF-β signalling, hybrid epithelial-mesenchymal phenotype and cancer stem cells Biomed Pharmacother 2019 111 119 30 10.1016/j.biopha.2018.12.05530579251Open DOISearch in Google Scholar

38Wang Y, Shi J, Chai K, Ying X, Zhou BP. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer 2017; 16: 10. doi: 10.1186/s12943-016-0577-4Wang Y Shi J Chai K Ying X Zhou BP Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation Mol Cancer 2017 16 10 10.1186/s12943-016-0577-4528272428137309Open DOISearch in Google Scholar

39Sim JJ, Jeong KY. Monitoring epithelial-mesenchymal transition of pancreatic cancer cells via investigation of mitochondrial dysfunction. Methods Protoc 2020; 3: 32. doi: 10.3390/mps3020032Sim JJ Jeong KY Monitoring epithelial-mesenchymal transition of pancreatic cancer cells via investigation of mitochondrial dysfunction Methods Protoc 2020 3 32 10.3390/mps3020032735969932349411Open DOISearch in Google Scholar

40Karicheva O, Rodriguez-Vargas JM, Wadier N, Martin-Hernandez K, Vauchelles R, Magroun N, et al. PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis. Oncotarget 2016; 7: 64109-23. doi: 10.18632/oncotarget.11627Karicheva O Rodriguez-Vargas JM Wadier N Martin-Hernandez K Vauchelles R Magroun N et al PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis Oncotarget 2016 7 64109 23 10.18632/oncotarget.11627532542927579892Open DOISearch in Google Scholar

41Sonowal H, Ramana KV. 4-Hydroxy-Trans-2-Nonenal in the regulation of anti-oxidative and pro-inflammatory signaling pathways. Oxid Med Cell Longev 2019; 2019: 5937326. doi: 10.1155/2019/5937326Sonowal H Ramana KV 4-Hydroxy-Trans-2-Nonenal in the regulation of anti-oxidative and pro-inflammatory signaling pathways Oxid Med Cell Longev 2019 2019 5937326 10.1155/2019/5937326687539931781341Open DOISearch in Google Scholar