Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells
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Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.
Abstract
Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.
참고문헌 (36)
- Chitty, J. L., "Recent advances in understanding the complexities of metastasis", F1000Res, 7, pp.F1000~ (2018)
- Lambert, A. W., "Emerging biological principles of metastasis", Cell, 168, pp.670~691 (2017)
- Fariz Nurwidya, "Epithelial Mesenchymal Transition in Drug Resistance and Metastasis of Lung Cancer", Cancer Research and Treatment, 44(3), pp.151~156 (2012), 대한암학회[DOI]
- Rotow, J., "Understanding and targeting resistance mechanisms in NSCLC", Nat. Rev. Cancer, 17, pp.637~658 (2017)
- Steeg, P. S., "Targeting metastasis", Nat. Rev. Cancer, 16, pp.201~218 (2016)
- Colak, S., "Targeting TGF-beta signaling in cancer", Trends Cancer, 3, pp.56~71 (2017)
- Gherardi, E., "Targeting MET in cancer : rationale and progress", Nat. Rev. Cancer, 12, pp.89~103 (2012)
- Dongre, A., "New insights into the mechanisms of epithelialmesenchymal transition and implications for cancer", Nat. Rev. Mol. Cell Biol, 20, pp.69~84 (2019)
- Eser, P. O., "TGFbeta pathway inhibition in the treatment of nonsmall cell lung cancer", Pharmacol. Ther, 184, pp.112~130 (2018)
- Neuzillet, C., "Targeting the TGFbeta pathway for cancer therapy", Pharmacol. Ther, 147, pp.22~31 (2015)
- Perlikos, F., "Key molecular mechanisms in lung cancer invasion and metastasis : a comprehensive review", Crit. Rev. Oncol. Hematol, 87, pp.1~11 (2013)
- Vazquez, P. F., "TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer", Clin. Exp. Metastasis, 30, pp.993~1007 (2013)
- Kwak, E. L., "Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer", N. Engl. J. Med, 363, pp.1693~1703 (2010)
- Ou, S. H., "Activity of crizotinib(PF02341066), a dual mesenchymal-epithelial transition(MET)and anaplastic lymphoma kinase(ALK)inhibitor, in a non-small cell lung cancer patient with de novo MET amplification", J. Thorac. Oncol, 6, pp.942~946 (2011)
- Solomon, B. J., "First-line crizotinib versus chemotherapy in ALK-positive lung cancer", N. Engl. J. Med, 371, pp.2167~2177 (2014)
- Zou, H. Y., "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms", Cancer Res, 67, pp.4408~4417 (2007)
- Shaw, A. T., "Crizotinib in ROS1-rearranged non-small-cell lung cancer", N. Engl. J. Med, 371, pp.1963~1971 (2014)
- Lin, J. J., "Targeting ALK : precision medicine takes on drug resistance", Cancer Discov, 7, pp.137~155 (2017)
- Sierra, J. R., "c-MET as a potential therapeutic target and biomarker in cancer", Ther. Adv. Med. Oncol, 3, pp.S21~S35 (2011)
- Spina, A., "HGF", c-MET axis in tumor microenvironment and metastasis formation, 2015, pp.3, 71~88
- Benedettini, E., "Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis", Am. J. Pathol, 177, pp.415~423 (2010)
- Finocchiaro, G., "Prognostic and predictive value of MET deregulation in non-small cell lung cancer", Ann. Transl. Med, 3, pp.83~ (2015)
- Salgia, R., "MET in lung cancer : biomarker selection based on scientific rationale", Mol. Cancer Ther, 16, pp.555~565 (2017)
- Costa, D. B., "Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases", J. Clin. Oncol, 33, pp.1881~1888 (2015)
- Zhang, I., "Targeting brain metastases in ALK-rearranged non-small-cell lung cancer", Lancet Oncol, 16, pp.e510~e521 (2015)
- Park, E. J., "Schisandrin B suppresses TGFbeta1 signaling by inhibiting Smad2", 3 and MAPK pathways, 2012, pp.83, 378~384
- Chun, J. N., "Schisandrin B suppresses TGFbeta1-induced stress fiber formation by inhibiting myosin light chain phosphorylation", J. Ethnopharmacol, 152, pp.364~371 (2014)
- Larsen, J. E., "ZEB1 drives epithelial-to-mesenchymal transition in lung cancer", J. Clin. Invest, 126, pp.3219~3235 (2016)
- Hong, S. W., "Immune profile by multiplexed immunohistochemistry associated with recurrence after chemoradiation in rectal cancer", J. Gastroenterol. Hepatol, 37, pp.542~550 (2022)
- Xu, J., "TGF-beta-induced epithelial to mesenchymal transition", Cell Res, 19, pp.156~172 (2009)
- Hao, Y., "TGF-beta-mediated epithelial-mesenchymal transition and cancer metastasis", Int. J. Mol. Sci, 20, pp.2767~ (2019)
- Rimkunas, V. M., "Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer : identification of a FIG-ROS1 fusion", Clin. Cancer Res, 18, pp.4449~4457 (2012)
- Yasuda, H., "Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer", J. Thorac. Oncol, 7, pp.1086~1090 (2012)
- Lamouille, S., "Molecular mechanisms of epithelialmesenchymal transition", Nat. Rev. Mol. Cell Biol, 15, pp.178~196 (2014)
- Zeisberg, M., "Biomarkers for epithelial-mesenchymal transitions", J. Clin. Invest, 119, pp.1429~1437 (2009)
- Kim, H. R., "Epithelial-mesenchymal transition leads to crizotinib resistance in H2228 lung cancer cells with EML4-ALK translocation", Mol. Oncol, 7, pp.1093~1102 (2013)