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Cellular and Molecular Biology

Matrix stiffening and acquired resistance to chemotherapy: concepts and clinical significance

British Journal of Cancer volume 126, pages 1253–1263 (2022)Cite this article

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Abstract

Extracellular matrix (ECM) refers to the non-cellular components of the tumour microenvironment, fundamentally providing a supportive scaffold for cellular anchorage and transducing signaling cues that orchestrate cellular behaviour and function. The ECM integrity is abrogated in several cases of cancer, ending in aberrant activation of a number of mechanotransduction pathways and induction of multiple tumorigenic events such as extended proliferation, cell death resistance, epithelial-mesenchymal transition and most importantly the development of chemoresistance. In this regard, the present study mainly aims to elucidate how the ECM-stiffening process may contribute to the development of chemoresistance during cancer progression and what pharmacological approaches are required for tackling this issue. Hence, the first section of this review explains the process of ECM stiffening and the ways it may affect biochemical pathways to induce chemoresistance in a clinic. In addition, the second part focuses on describing some of the most important pharmacological agents capable of targeting ECM components and underlying pathways for overcoming ECM-induced chemoresistance. Finally, the third part discusses the obtained results from the application of these agents in the clinic for overcoming chemoresistance.

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Fig. 1: ECM stiffening and hallmarks of acquired resistance to chemotherapy.
Fig. 2: A general scheme representing how ECM stiffening and cancer cell interaction may result in chemoresistance development.
Fig. 3: Alterations in signaling pathways induced by matrix stiffening in the tumour microenvironment and related therapeutic approaches.

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References

  1. Hayes DF, Schott AF. Neoadjuvant chemotherapy: what are the benefits for the patient and for the investigator? J Natl Cancer Inst Monogr. 2015;2015:36–39.

    Article  PubMed  Google Scholar 

  2. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.

    Article  CAS  PubMed  Google Scholar 

  3. Marquette C, Nabell L. Chemotherapy-resistant metastatic breast cancer. Curr Treat Options Oncol. 2012;13:263–75.

    Article  PubMed  Google Scholar 

  4. Farahmand L, Merikhian P, Jalili N, Darvishi B, Majidzadeh AK. Significant role of MUC1 in development of resistance to currently existing anti-cancer therapeutic agents. Curr Cancer Drug Targets. 2018;18:737–48.

    Article  CAS  PubMed  Google Scholar 

  5. Darvishi B, Majidzadeh AK, Ghadirian R, Mosayebzadeh M, Farahmand L. Recruited bone marrow derived cells, local stromal cells and IL-17 at the front line of resistance development to anti-VEGF targeted therapies. Life Sci. 2019;217:34–40.

    Article  CAS  PubMed  Google Scholar 

  6. Mahdi A, Darvishi B, Majidzadeh AK, Salehi M, Farahmand L. Challenges facing antiangiogenesis therapy: the significant role of hypoxia-inducible factor and MET in development of resistance to anti-vascular endothelial growth factor-targeted therapies. J Cell Physiol. 2019;234:5655–63.

    Article  CAS  PubMed  Google Scholar 

  7. Darvishi B, Farahmand L, Eslami SZ, Majidzadeh AK. NF-kappaB as the main node of resistance to receptor tyrosine kinase inhibitors in triple-negative breast cancer. Tumour Biol. 2017;39:1010428317706919.

    Article  PubMed  CAS  Google Scholar 

  8. Brasseur K, Gevry N, Asselin E. Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget. 2017;8:4008–42.

    Article  PubMed  Google Scholar 

  9. Salaritabar A, Berindan-Neagoe I, Darvish B, Hadjiakhoondi F, Manayi A, Devi KP, et al. Targeting Hedgehog signaling pathway: paving the road for cancer therapy. Pharmacol Res. 2019;141:466–80.

    Article  CAS  PubMed  Google Scholar 

  10. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Paszek MJ, Weaver VM. The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia. 2004;9:325–42.

    Article  PubMed  Google Scholar 

  12. Kass L, Erler JT, Dembo M, Weaver VM. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol. 2007;39:1987–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4:165–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mierke CT, Sauer F, Grosser S, Puder S, Fischer T, Kas JA. The two faces of enhanced stroma: Stroma acts as a tumor promoter and a steric obstacle. NMR Biomed. 2018;31:e3831.

    Article  PubMed  Google Scholar 

  15. Wei B, Zhou X, Liang C, Zheng X, Lei P, Fang J, et al. Human colorectal cancer progression correlates with LOX-induced ECM stiffening. Int J Biol Sci. 2017;13:1450–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 2015;33:230–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Farhood B, Najafi M, Mortezaee K. Cancer‐associated fibroblasts: secretions, interactions, and therapy. J Cell Biochem. 2019;120:2791–2800.

    Article  CAS  PubMed  Google Scholar 

  18. Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiology (Bethesda). 2010;25:85–101.

    CAS  Google Scholar 

  19. de la Mare JA, Jurgens T, Edkins AL. Extracellular Hsp90 and TGFbeta regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model. BMC Cancer. 2017;17:202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15:786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee J, Condello S, Yakubov B, Emerson R, Caperell-Grant A, Hitomi K, et al. Tissue transglutaminase mediated tumor-stroma interaction promotes pancreatic cancer progression. Clin Cancer Res. 2015;21:4482–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011;178:1221–32.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4:1–15.

    Article  CAS  Google Scholar 

  24. Kondo S, Kubota S, Shimo T, Nishida T, Yosimichi G, Eguchi T, et al. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis. 2002;23:769–76.

    Article  CAS  PubMed  Google Scholar 

  25. Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005;65:5278–83.

    Article  CAS  PubMed  Google Scholar 

  26. Andersson P, Yang Y, Hosaka K, Zhang Y, Fischer C, Braun H, et al. Molecular mechanisms of IL-33–mediated stromal interactions in cancer metastasis. JCI Insight. 2018;3:e122375.

  27. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15:786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015;44:247–54.

    Article  PubMed  CAS  Google Scholar 

  29. Nukuda A, Sasaki C, Ishihara S, Mizutani T, Nakamura K, Ayabe T, et al. Stiff substrates increase YAP-signaling-mediated matrix metalloproteinase-7 expression. Oncogenesis. 2015;4:e165–e165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dangi-Garimella S, Krantz SB, Barron MR, Shields MA, Heiferman MJ, Grippo PJ, et al. Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP–mediated expression of HMGA2. Cancer Res. 2011;71:1019–28.

    Article  CAS  PubMed  Google Scholar 

  31. Pratt J, Annabi B. Induction of autophagy biomarker BNIP3 requires a JAK2/STAT3 and MT1-MMP signaling interplay in Concanavalin-A-activated U87 glioblastoma cells. Cell Signal. 2014;26:917–24.

    Article  CAS  PubMed  Google Scholar 

  32. Akers WJ, Xu B, Lee H, Sudlow GP, Fields GB, Achilefu S, et al. Detection of MMP-2 and MMP-9 activity in vivo with a triple-helical peptide optical probe. Bioconjugate Chem. 2012;23:656–63.

    Article  CAS  Google Scholar 

  33. Huang Y, Yu H, Lei H, Xie C, Zhong Y. Matrix metalloproteinase 7 is a useful marker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. Med Oncol. 2014;31:824.

    Article  PubMed  CAS  Google Scholar 

  34. Almendro V, Ametller E, García-Recio S, Collazo O, Casas I, Augé JM, et al. The role of MMP7 and its cross-talk with the FAS/FASL system during the acquisition of chemoresistance to oxaliplatin. PLoS ONE. 2009;4:e4728.

  35. Liu H, Zhang T, Wu B, Huang J, Zhou Y, Zhu J. Chronic exposure to exogenous matrilysin induces chemoresistance and enhances Bcl-2 expression in A549 lung adenocarcinoma cells. Mol Biol Rep. 2009;36:2099.

    Article  CAS  PubMed  Google Scholar 

  36. Smith-Mungo LI, Kagan HM. Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol. 1998;16:387–98.

    Article  CAS  PubMed  Google Scholar 

  37. Rossow L, Veitl S, Vorlova S, Wax JK, Kuhn AE, Maltzahn V, et al. LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy. Oncogene. 2018;37:4921–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15:35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maxwell P, Dachs G, Gleadle J, Nicholls L, Harris A, Stratford I, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA. 1997;94:8104–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baker A-M, Bird D, Welti JC, Gourlaouen M, Lang G, Murray GI, et al. Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis. Cancer Res. 2013;73:583–94.

    Article  CAS  PubMed  Google Scholar 

  41. Zaffryar-Eilot S, Marshall D, Voloshin T, Bar-Zion A, Spangler R, Kessler O, et al. Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours. Carcinogenesis. 2013;34:2370–9.

    Article  CAS  PubMed  Google Scholar 

  42. Schütze F, Röhrig F, Vorlová S, Gätzner S, Kuhn A, Ergün S, et al. Inhibition of lysyl oxidases improves drug diffusion and increases efficacy of cytotoxic treatment in 3D tumor models. Sci Rep. 2015;5:1–13.

    Article  CAS  Google Scholar 

  43. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Berrier AL, Yamada KM. Cell–matrix adhesion. J Cell Physiol. 2007;213:565–73.

    Article  CAS  PubMed  Google Scholar 

  45. Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5:816–26.

    Article  CAS  PubMed  Google Scholar 

  46. Eke I, Storch K, Krause M, Cordes N. Cetuximab attenuates its cytotoxic and radiosensitizing potential by inducing fibronectin biosynthesis. Cancer Res. 2013;73:5869–79.

    Article  CAS  PubMed  Google Scholar 

  47. Steglich A, Vehlow A, Eke I, Cordes N. α integrin targeting for radiosensitization of three-dimensionally grown human head and neck squamous cell carcinoma cells. Cancer Lett. 2015;357:542–8.

    Article  CAS  PubMed  Google Scholar 

  48. Nam J-M, Ahmed KM, Costes S, Zhang H, Onodera Y, Olshen AB, et al. 1-Integrin via NF-κB signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancer. Breast Cancer Res. 2013;15:R60.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ahmed KM, Zhang H, Park CC. NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells. Cancer Res. 2013;73:3737–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ducassou A, Uro-Coste E, Verrelle P, Filleron T, Benouaich-Amiel A, Lubrano V, et al. vβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I–II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma. Eur J Cancer. 2013;49:2161–9.

    Article  CAS  PubMed  Google Scholar 

  51. Lanvin O, Monferran S, Delmas C, Couderc B, Toulas C, Cohen-Jonathan-Moyal E. Radiation-induced mitotic cell death and glioblastoma radioresistance: a new regulating pathway controlled by integrin-linked kinase, hypoxia-inducible factor 1alpha and survivin in U87 cells. Eur J Cancer. 2013;49:2884–91.

    Article  CAS  PubMed  Google Scholar 

  52. Sørensen BH, Rasmussen LJH, Broberg BS, Klausen TK, Sauter DPR, Lambert IH, et al. Integrin β1, osmosensing, and chemoresistance in mouse ehrlich carcinoma cells. Cell Physiol Biochem. 2015;36:111–32.

    Article  PubMed  CAS  Google Scholar 

  53. Howe GA, Addison CL. β1 integrin: an emerging player in the modulation of tumorigenesis and response to therapy. Cell Adhes Migr. 2012;6:71–77.

    Article  Google Scholar 

  54. Janouskova H, Ray A-M, Noulet F, Lelong-Rebel I, Choulier L, Schaffner F, et al. Activation of p53 pathway by Nutlin-3a inhibits the expression of the therapeutic target α5 integrin in colon cancer cells. Cancer Lett. 2013;336:307–18.

    Article  CAS  PubMed  Google Scholar 

  55. Han S, Li Z, Master L, Master Z, Wu A. Exogenous IGFBP-2 promotes proliferation, invasion, and chemoresistance to temozolomide in glioma cells via the integrin β1-ERK pathway. Br J Cancer. 2014;111:1400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Naci D, Vuori K, Aoudjit, F. Alpha2beta1 integrin in cancer development and chemoresistance. Semin Cancer Biol. 2015;35:145–53.

  57. Fedorenko IV, Abel EV, Koomen JM, Fang B, Wood ER, Chen YA, et al. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene. 2016;35:1225–35.

    Article  CAS  PubMed  Google Scholar 

  58. Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell. 2015;27:574–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yuan J, Liu M, Yang L, Tu G, Zhu Q, Chen M, et al. Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells. Breast Cancer Res. 2015;17:69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. McGrail DJ, Khambhati NN, Qi MX, Patel KS, Ravikumar N, Brandenburg CP, et al. Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner. Sci Rep. 2015;5:9529.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25:234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Eke I, Zscheppang K, Dickreuter E, Hickmann L, Mazzeo E, Unger K, et al. Simultaneous β1 integrin-EGFR targeting and radiosensitization of human head and neck cancer. J Natl Cancer Inst. 2015;107:dju419.

  63. Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, et al. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 2013;73:6243–53.

    Article  CAS  PubMed  Google Scholar 

  64. Ju L, Zhou C. Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer. Cancer Cell Int. 2013;13:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gadiya M, Chakraborty G. Signaling by discoidin domain receptor 1 in cancer metastasis. Cell Adhes Migr. 2018;12:315–23.

    CAS  Google Scholar 

  66. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1:13–23.

    Article  CAS  PubMed  Google Scholar 

  67. Ambrogio C, Darbo E, Lee SW, Santamaría D. A putative role for Discoidin Domain Receptor 1 in cancer chemoresistance. Cell Adhes Migr. 2018;12:394–7.

    CAS  Google Scholar 

  68. Yang SH, Baek HA, Lee HJ, Park HS, Jang KY, Kang MJ, et al. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncol Rep. 2010;24:311–9.

    CAS  PubMed  Google Scholar 

  69. Wang J, Hu K, Guo J, Cheng F, Lv J, Jiang W, et al. Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK. Nat Commun. 2016;7:1–13.

    Google Scholar 

  70. Leal AS, Misek SA, Lisabeth EM, Neubig RR, Liby KT. The Rho/MRTF pathway inhibitor CCG-222740 reduces stellate cell activation and modulates immune cell populations in Kras G12D; Pdx1-Cre (KC) mice. Sci Rep. 2019;9:1–12.

    Article  Google Scholar 

  71. Vennin C, Chin VT, Warren SC, Lucas MC, Herrmann D, Magenau A, et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med. 2017;9:eaai8504.

  72. Haak AJ, Appleton KM, Lisabeth EM, Misek SA, Ji Y, Wade SM, et al. Pharmacological inhibition of myocardin-related transcription factor pathway blocks lung metastases of RhoC-overexpressing melanoma. Mol Cancer Ther. 2017;16:193–204.

    Article  CAS  PubMed  Google Scholar 

  73. Laios A, Mohamed BM, Kelly L, Flavin R, Finn S, McEvoy L, et al. Pre-treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening. Int J Mol Sci. 2013;14:2085–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637–46.

    Article  CAS  PubMed  Google Scholar 

  75. Shalinsky D, Brekken J, Zou H, McDermott C, Forsyth P, Edwards D, et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann N Y Acad Sci. 1999;878:236–70.

    Article  CAS  PubMed  Google Scholar 

  76. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, et al. Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology. 2015;149:1932–43. e1939.

    Article  CAS  PubMed  Google Scholar 

  78. Duluc C, Moatassim‐Billah S, Chalabi‐Dchar M, Perraud A, Samain R, Breibach F, et al. Pharmacological targeting of the protein synthesis mTOR/4E‐BP1 pathway in cancer‐associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Mol Med. 2015;7:735–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Aksorn N, Chanvorachote P. Integrin as a molecular target for anti-cancer approaches in lung cancer. Anticancer Res. 2019;39:541–8.

    Article  CAS  PubMed  Google Scholar 

  80. Fisher ML, Grun D, Adhikary G, Xu W, Eckert RL. Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells. Oncotarget. 2017;8:110257.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Scott LJ, Goa KL. Verteporfin. Drugs Aging. 2000;16:139–46.

    Article  CAS  PubMed  Google Scholar 

  82. Keam SJ, Scott LJ, Curran MP. Verteporfin. Drugs. 2003;63:2521–54.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang H, Ramakrishnan SK, Triner D, Centofanti B, Maitra D, Győrffy B, et al. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. Sci Signal. 2015;8:ra98–ra98.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee S-J, Anders RA, et al. Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dasari VR, Mazack V, Feng W, Nash J, Carey DJ, Gogoi R. Verteporfin exhibits YAP-independent anti-proliferative and cytotoxic effects in endometrial cancer cells. Oncotarget. 2017;8:28628.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Tao Y, Cai F, Shan L, Jiang H, Ma L, Yu Y. The Hippo signaling pathway: an emerging anti-cancer drug target. Discov Med. 2017;24:7–18.

    PubMed  Google Scholar 

  87. Oku Y, Nishiya N, Shito T, Yamamoto R, Yamamoto Y, Oyama C, et al. Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers. FEBS Open Biol. 2015;5:542–9.

    Article  CAS  Google Scholar 

  88. Xia H, Dai X, Yu H, Zhou S, Fan Z, Wei G, et al. EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy. Cell Death Dis. 2018;9:1–12.

    Article  CAS  Google Scholar 

  89. Matusewicz L, Meissner J, Toporkiewicz M, Sikorski AF. The effect of statins on cancer cells. Tumor Biol. 2015;36:4889–904.

    Article  CAS  Google Scholar 

  90. Gay CM, Balaji K, Byers LA. Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer. 2017;116:415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Heestand G, Pipas J, Valone F, McMullen A, Gadea P, Williams D, et al. A phase I trial of the monoclonal antibody FG-3019 to connective tissue growth factor (CTGF) in locally advanced or metastatic pancreatic cancer. J Clin Oncol. 2011;29:269–269.

    Article  Google Scholar 

  92. Kitajima S, Asahina H, Chen T, Guo S, Quiceno LG, Cavanaugh JD, et al. Overcoming resistance to dual innate immune and MEK inhibition downstream of KRAS. Cancer Cell. 2018;34:439–52. e436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zanconato F, Battilana G, Forcato M, Filippi L, Azzolin L, Manfrin A, et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat Med. 2018;24:1599–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Xu Y, Vakoc CR. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harb Perspect Med. 2017;7:a026674.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. 2016;19:45–50.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Elster D, Tollot M, Schlegelmilch K, Ori A, Rosenwald A, Sahai E, et al. TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells. Nat Commun. 2018;9:1–16.

    CAS  Google Scholar 

  97. Kim M, Kim T, Johnson RL, Lim D-S. Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ. Cell Rep. 2015;11:270–82.

    Article  CAS  PubMed  Google Scholar 

  98. Oh H, Slattery M, Ma L, White KP, Mann RS, Irvine KD. Yorkie promotes transcription by recruiting a histone methyltransferase complex. Cell Rep. 2014;8:449–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mullamitha SA, Ton NC, Parker GJ, Jackson A, Julyan PJ, Roberts C, et al. Phase I evaluation of a fully human anti–αv integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res. 2007;13:2128–35.

    Article  CAS  PubMed  Google Scholar 

  100. Ning S, Nemeth JA, Hanson RL, Forsythe K, Knox SJ. Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo. Mol Cancer Ther. 2008;7:1569–78.

    Article  CAS  PubMed  Google Scholar 

  101. Doñate F, Parry GC, Shaked Y, Hensley H, Guan X, Beck I, et al. Pharmacology of the novel antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2): observation of a U-shaped dose-response curve in several preclinical models of angiogenesis and tumor growth. Clin Cancer Res. 2008;14:2137–44.

    Article  PubMed  Google Scholar 

  102. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, et al. A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med. 2007;5:61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Schultze A, Decker S, Otten J, Horst AK, Vohwinkel G, Schuch G, et al. TAE226-mediated inhibition of focal adhesion kinase interferes with tumor angiogenesis and vasculogenesis. Invest N Drugs. 2010;28:825–33.

    Article  CAS  Google Scholar 

  104. Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, et al. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008;68:1935–44.

    Article  CAS  PubMed  Google Scholar 

  105. Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature. 1996;383:547–50.

    Article  CAS  PubMed  Google Scholar 

  106. Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res. 2009;11:R68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Sun H, Pisle S, Gardner ER, Figg I. William D. Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther. 2010;10:38–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bagi CM, Christensen J, Cohen DP, Roberts WG, Wilkie D, Swanson T, et al. Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model. Cancer Biol Ther. 2009;8:856–65.

    Article  CAS  PubMed  Google Scholar 

  109. Hiscox S, Barnfather P, Hayes E, Bramble P, Christensen J, Nicholson RI, et al. Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells. Breast Cancer Res Treat. 2011;125:659–69.

    Article  CAS  PubMed  Google Scholar 

  110. Tanjoni I, Walsh C, Uryu S, Tomar A, Nam J-O, Mielgo A, et al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol Ther. 2010;9:764–77.

    Article  CAS  PubMed  Google Scholar 

  111. Schaller MD, Frisch SM. PND-1186 FAK inhibitor selectively promotes tumore cell apoptosis in three-dimensional environments. Cancer Biol Ther. 2010;9:791–3.

    Article  CAS  PubMed  Google Scholar 

  112. Walsh C, Tanjoni I, Uryu S, Tomar A, Nam J-O, Luo H, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther. 2010;9:778–90.

    Article  CAS  PubMed  Google Scholar 

  113. Golubovskaya VM, Nyberg C, Zheng M, Kweh F, Magis A, Ostrov D, et al. A small molecule inhibitor, 1, 2, 4, 5-benzenetetraamine tetrahydrochloride, targeting the y397 site of focal adhesion kinase decreases tumor growth. J Med Chem. 2008;51:7405–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zheng D, Golubovskaya V, Kurenova E, Wood C, Massoll NA, Ostrov D, et al. A novel strategy to inhibit FAK and IGF‐1R decreases growth of pancreatic cancer xenografts. Mol Carcinog. 2010;49:200–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hochwald SN, Nyberg C, Zheng M, Zheng D, Wood C, Massoll NA, et al. A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer. Cell Cycle. 2009;8:2435–43.

    Article  CAS  PubMed  Google Scholar 

  116. Wintzell M, Hjerpe E, Lundqvist EÅ, Shoshan M. Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites. BMC Cancer. 2012;12:359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer—trials and tribulations. Science. 2002;295:2387–92.

    Article  CAS  PubMed  Google Scholar 

  119. Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh V, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol. 2002;20:4434–9.

    Article  CAS  PubMed  Google Scholar 

  120. Mack GS, Marshall A. Lost in migration. Nat Biotechnol. 2010;28:214–29.

    Article  CAS  PubMed  Google Scholar 

  121. Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2014;13:63–79.

    Article  CAS  PubMed  Google Scholar 

  122. Finn RS, Bengala C, Ibrahim N, Roché H, Sparano J, Strauss LC, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011;17:6905–13.

    Article  CAS  PubMed  Google Scholar 

  123. Twardowski PW, Beumer JH, Chen C, Kraft AS, Chatta GS, Mitsuhashi M, et al. A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. Anticancer Drugs. 2013;24:743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Spreafico A, Chi KN, Sridhar SS, Smith DC, Carducci MA, Kavsak P, et al. A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients. Invest N Drugs. 2014;32:1005–16.

    Article  CAS  Google Scholar 

  125. Johnson ML, Riely GJ, Rizvi NA, Azzoli CG, Kris MG, Sima CS, et al. Phase II trial of dasatinib for patients with acquired resistance to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib. J Thorac Oncol. 2011;6:1128–31.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Monia BP, Johnston JF, Geiger T, Muller M, Fabbro D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nat Med. 1996;2:668–75.

    Article  CAS  PubMed  Google Scholar 

  127. Sun S, Irvine KD. Cellular organization and cytoskeletal regulation of the Hippo signaling network. Trends Cell Biol. 2016;26:694–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Guo W, Wei B, Chen T, Xu X, Ruan F, Xiang M. The Na+/K+ ATPase inhibitor ouabain attenuates stemness and chemoresistance of osteosarcoma cells. Med Sci Monit Int Med J Exp Clin Res. 2019;25:9426.

    CAS  Google Scholar 

  129. Javadi S, Rostamizadeh K, Hejazi J, Parsa M, Fathi M. Curcumin mediated down‐regulation of αVβ3 integrin and up‐regulation of pyruvate dehydrogenase kinase 4 (PDK4) in Erlotinib resistant SW480 colon cancer cells. Phytother Res. 2018;32:355–64.

    Article  CAS  PubMed  Google Scholar 

  130. Chen P, Huang H-P, Wang Y, Jin J, Long W-G, Chen K, et al. Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death. J Exp Clin Cancer Res. 2019;38:1–17.

    Article  Google Scholar 

  131. Hehlgans S, Lange I, Eke I, Cordes N. 3D cell cultures of human head and neck squamous cell carcinoma cells are radiosensitized by the focal adhesion kinase inhibitor TAE226. Radiother Oncol. 2009;92:371–8.

    Article  CAS  PubMed  Google Scholar 

  132. Bagi CM, Roberts GW, Andresen CJ. Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases. Cancer. 2008;112:2313–21.

    Article  CAS  PubMed  Google Scholar 

  133. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Das S, Ongusaha PP, Yang YS, Park J-M, Aaronson SA, Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-κB pathway activation. Cancer Res. 2006;66:8123–30.

    Article  CAS  PubMed  Google Scholar 

  135. Morimatsu M, Yamashita E, Seno S, Sudo T, Kikuta J, Mizuno H, et al. Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway. Inflamm Regen. 2020;40:1–9.

    Article  CAS  Google Scholar 

  136. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran

    Behrad Darvishi, Mohammad Reza Eisavand, Keivan Majidzadeh-A & Leila Farahmand

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  1. Behrad Darvishi
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BD, MRE, KMA and LF wrote the manuscript. BD and MRE collected and organised the data, and designed the figures. Further, KMA and LF edited the manuscript for scientific errors. All authors read and approved the manuscript in its final format.

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Correspondence to Leila Farahmand.

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Darvishi, B., Eisavand, M.R., Majidzadeh-A, K. et al. Matrix stiffening and acquired resistance to chemotherapy: concepts and clinical significance. Br J Cancer 126, 1253–1263 (2022). https://doi.org/10.1038/s41416-021-01680-8

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