Abstract
Mutation-selective drugs constitute a great advancement in personalized anticancer treatment with increased quality of life and overall survival in cancers. However, the high adaptability and evasiveness of cancers can lead to disease progression and the development of drug resistance, which cause recurrence and metastasis. A common characteristic in advanced neoplastic cancers is the epithelial-mesenchymal transition (EMT) which is strongly interconnected with H2O2 signaling, increased motility and invasiveness. H2O2 relays its signal through the installation of oxidative posttranslational modifications on cysteines. The increased H2O2 levels that are associated with an EMT confer a heightened sensitivity towards the induction of ferroptosis as a recently discovered vulnerability.
Funding source: Fonds der Chemischen Industrie 10.13039/100007215
Funding source: LMUexcellent Junior Researcher Fund 10.13039/501100005722
Funding source: DFG SPP2306 10.13039/501100001659
Award Identifier / Grant number: KO 5903/2-1
Funding source: Excellence Strategy of the Federal Government and the Länder
About the authors
Anna V. Milton grew up in the Swedish countryside close to Vimmerby in Småland. To follow her academic interests, she moved to Uppsala where she obtained a B.Sc. in biomedicine followed by a M.Sc. in molecular medicine. Anna performed her Master’s thesis at the Biomedical Center at the Ludwig Maximilian University of Munich where she studied the epigenetic control of endogenous retroviruses. Equipped with a rigid and broad background in biomedical research, Anna’s specific interests lie in uncovering disease mechanisms. This led her to pursue a PhD in the Konrad laboratory, where she uses (chemo)proteomics methods to uncover vulnerabilities in therapy-resistant cancer cells for the development of novel drugs to treat advanced Non-Small Cell Lung Cancer.
David B. Konrad studied chemistry and biochemistry at the Ludwig Maximilian University (LMU) Munich and received his M.Sc. in 2013. During his Master’s studies, he worked as a visiting researcher in the group of Dean Toste at the University of California, Berkeley and the group of Benjamin List at the Max Planck Institute for Coal Research in Mülheim a. d. Ruhr. In 2014, David joined the group of Dirk Trauner for his graduate studies to work towards an asymmetric synthesis of tetrodotoxin and methods to red-shift photopharmaceuticals. After graduating in 2018 summa cum laude, David moved to the Scripps Research Institute in La Jolla as a postdoctoral fellow under the guidance of Benjamin Cravatt. As part of the return phase of his fellowship, David joined the group of Ivan Huc at the Department of Pharmacy of the LMU Munich, where he transitioned to an independent group leader in 2021.
Acknowledgements
The authors are grateful to Prof. Dr. Ivan Huc for his strong support and mentorship. Figures in this manuscript were, in part, created with BioRender.com.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: DBK acknowledges funding from the Fonds der Chemischen Industrie through a Liebig Fellowship, the DFG SPP2306 (KO 5903/2-1) and the LMUexcellent Junior Researcher Fund which is supported by the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder. AVM thanks the Department of Pharmacy for her Ph.D. position.
-
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
Akter, S., Fu, L., Jung, Y., Conte, M.L., Lawson, J.R., Lowther, W.T., Sun, R., Liu, K., Yang, J., and Carroll, K.S. (2018). Chemical proteomics reveals new targets of cysteine sulfinic acid reductase. Nat. Chem. Biol. 14: 995–1004, https://doi.org/10.1038/s41589-018-0116-2.Search in Google Scholar PubMed PubMed Central
Bak, D.W., Bechtel, T.J., Falco, J.A., and Weerapana, E. (2019). Cysteine reactivity across the subcellular universe. Curr. Opin. Chem. Biol. 48: 96–105, https://doi.org/10.1016/j.cbpa.2018.11.002.Search in Google Scholar PubMed PubMed Central
Battistelli, C., Cicchini, C., Santangelo, L., Tramontano, A., Grassi, L., Gonzalez, F.J., de Nonno, V., Grassi, G., Amicone, L., and Tripodi, M. (2017). The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene 36: 942–955, https://doi.org/10.1038/onc.2016.260.Search in Google Scholar PubMed PubMed Central
Birben, E., Sahiner, U.M., Sackesen, C., Erzurum, S., and Kalayci, O. (2012). Oxidative stress and antioxidant defense. World Allergy Organ. J. 5: 9–19, https://doi.org/10.1097/wox.0b013e3182439613.Search in Google Scholar PubMed PubMed Central
Blandin Knight, S., Crosbie, P.A., Balata, H., Chudziak, J., Hussell, T., and Dive, C. (2017). Progress and prospects of early detection in lung cancer. Open Biol. 7, https://doi.org/10.1098/rsob.170070.Search in Google Scholar PubMed PubMed Central
Bocci, F., Tripathi, S.C., Vilchez Mercedes, S.A., George, J.T., Casabar, J.P., Wong, P.K., Hanash, S.M., Levine, H., Onuchic, J.N., and Jolly, M.K. (2019). NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. Integr. Biol. (Camb.) 11: 251–263, https://doi.org/10.1093/intbio/zyz021.Search in Google Scholar PubMed PubMed Central
Boudreau, H.E., Casterline, B.W., Rada, B., Korzeniowska, A., and Leto, T.L. (2012). Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells. Free Radic. Biol. Med. 53: 1489–1499, https://doi.org/10.1016/j.freeradbiomed.2012.06.016.Search in Google Scholar PubMed PubMed Central
Boumahdi, S. and de Sauvage, F.J. (2020). The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19: 39–56, https://doi.org/10.1038/s41573-019-0044-1.Search in Google Scholar PubMed
Brandes, R.P., Weissmann, N., and Schroder, K. (2014). Nox family NADPH oxidases: molecular mechanisms of activation. Free Radic. Biol. Med. 76: 208–226, https://doi.org/10.1016/j.freeradbiomed.2014.07.046.Search in Google Scholar PubMed
Brigelius-Flohe, R. and Maiorino, M. (2013). Glutathione peroxidases. Biochim. Biophys. Acta 1830: 3289–3303, https://doi.org/10.1016/j.bbagen.2012.11.020.Search in Google Scholar PubMed
Buck, T., Hack, C.T., Berg, D., Berg, U., Kunz, L., and Mayerhofer, A. (2019). The NADPH oxidase 4 is a major source of hydrogen peroxide in human granulosa-lutein and granulosa tumor cells. Sci. Rep. 9: 3585, https://doi.org/10.1038/s41598-019-40329-8.Search in Google Scholar
Cannito, S., Novo, E., di Bonzo, L.V., Busletta, C., Colombatto, S., and Parola, M. (2010). Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease. Antioxid. Redox Signal. 12: 1383–1430, https://doi.org/10.1089/ars.2009.2737.Search in Google Scholar
Castano, Z., San Juan, B.P., Spiegel, A., Pant, A., DeCristo, M.J., Laszewski, T., Ubellacker, J.M., Janssen, S.R., Dongre, A., Reinhardt, F., et al.. (2018). IL-1beta inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat. Cell Biol. 20: 1084–1097, https://doi.org/10.1038/s41556-018-0173-5.Search in Google Scholar
Chaffer, C.L., Brennan, J.P., Slavin, J.L., Blick, T., Thompson, E.W., and Williams, E.D. (2006). Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 66: 11271–11278, https://doi.org/10.1158/0008-5472.can-06-2044.Search in Google Scholar
Chaffer, C.L., Marjanovic, N.D., Lee, T., Bell, G., Kleer, C.G., Reinhardt, F., D’Alessio, A.C., Young, R.A., and Weinberg, R.A. (2013). Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154: 61–74, https://doi.org/10.1016/j.cell.2013.06.005.Search in Google Scholar
Chen, B., Li, L., Li, M., and Wang, X. (2020). HIF1A expression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Cell. Oncol. 43: 877–888, https://doi.org/10.1007/s13402-020-00534-4.Search in Google Scholar
Chen, C.Y., Willard, D., and Rudolph, J. (2009). Redox regulation of SH2-domain-containing protein tyrosine phosphatases by two backdoor cysteines. Biochemistry 48: 1399–1409, https://doi.org/10.1021/bi801973z.Search in Google Scholar
Chen, X., Comish, P.B., Tang, D., and Kang, R. (2021). Characteristics and biomarkers of ferroptosis. Front. Cell Dev. Biol. 9: 637162, https://doi.org/10.3389/fcell.2021.637162.Search in Google Scholar
Chiarugi, P. and Cirri, P. (2003). Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem. Sci. 28: 509–514, https://doi.org/10.1016/s0968-0004(03)00174-9.Search in Google Scholar
Conrad, M. and Pratt, D.A. (2019). The chemical basis of ferroptosis. Nat. Chem. Biol. 15: 1137–1147, https://doi.org/10.1038/s41589-019-0408-1.Search in Google Scholar PubMed
Consortium, A.P.G. (2017). AACR project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7: 818–831, https://doi.org/10.1158/2159-8290.CD-17-0151.Search in Google Scholar PubMed PubMed Central
Cortot, A.B. and Janne, P.A. (2014). Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur. Respir. Rev. 23: 356–366, https://doi.org/10.1183/09059180.00004614.Search in Google Scholar PubMed
Cozza, G., Rossetto, M., Bosello-Travain, V., Maiorino, M., Roveri, A., Toppo, S., Zaccarin, M., Zennaro, L., and Ursini, F. (2017). Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: the polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center. Free Radic. Biol. Med. 112: 1–11, https://doi.org/10.1016/j.freeradbiomed.2017.07.010.Search in Google Scholar PubMed
Cross, D.A.E., Ashton, S.E., Ghiorghiu, S., Eberlein, C., Nebhan, C.A., Spitzler, P.J., Orme, J.P., Finlay, M.R.V., Ward, R.A., Mellor, M.J., et al.. (2014). AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4: 1046–1061, https://doi.org/10.1158/2159-8290.cd-14-0337.Search in Google Scholar PubMed PubMed Central
de Rezende, F.F., Martins Lima, A., Niland, S., Wittig, I., Heide, H., Schroder, K., and Eble, J.A. (2012). Integrin alpha7beta1 is a redox-regulated target of hydrogen peroxide in vascular smooth muscle cell adhesion. Free Radic. Biol. Med. 53: 521–531, https://doi.org/10.1016/j.freeradbiomed.2012.05.032.Search in Google Scholar PubMed
Dean, M., Fojo, T., and Bates, S. (2005). Tumour stem cells and drug resistance. Nat. Rev. Cancer 5: 275–284, https://doi.org/10.1038/nrc1590.Search in Google Scholar PubMed
Dillekås, H., Rogers, M.S., and Straume, O. (2019). Are 90% of deaths from cancer caused by metastases? Cancer Med. 8: 5574–5576.10.1002/cam4.2474Search in Google Scholar PubMed PubMed Central
Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., Yang, W.S., et al.. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149: 1060–1072, https://doi.org/10.1016/j.cell.2012.03.042.Search in Google Scholar PubMed PubMed Central
Dixon, S.J. and Stockwell, B.R. (2014). The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10: 9–17, https://doi.org/10.1038/nchembio.1416.Search in Google Scholar PubMed
Doll, S., Freitas, F.P., Shah, R., Aldrovandi, M., da Silva, M.C., Ingold, I., Goya Grocin, A., Xavier da Silva, T.N., Panzilius, E., Scheel, C.H., et al.. (2019). FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575: 693–698, https://doi.org/10.1038/s41586-019-1707-0.Search in Google Scholar PubMed
Drapela, S., Bouchal, J., Jolly, M.K., Culig, Z., and Soucek, K. (2020). ZEB1: a critical regulator of cell plasticity, DNA damage response, and therapy resistance. Front. Mol. Biosci. 7: 36, https://doi.org/10.3389/fmolb.2020.00036.Search in Google Scholar PubMed PubMed Central
Druker, B.J., Guilhot, F., O’Brien, S.G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M.W., Silver, R.T., Goldman, J.M., Stone, R.M., et al.. (2006). Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355: 2408–2417, https://doi.org/10.1056/nejmoa062867.Search in Google Scholar PubMed
Druker, B.J., Talpaz, M., Resta, D.J., Peng, B., Buchdunger, E., Ford, J.M., Lydon, N.B., Kantarjian, H., Capdeville, R., Ohno-Jones, S., et al.. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344: 1031–1037, https://doi.org/10.1056/nejm200104053441401.Search in Google Scholar PubMed
Eaton, J.K., Furst, L., Ruberto, R.A., Moosmayer, D., Hilpmann, A., Ryan, M.J., Zimmermann, K., Cai, L.L., Niehues, M., Badock, V., et al.. (2020). Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol. 16: 497–506, https://doi.org/10.1038/s41589-020-0501-5.Search in Google Scholar PubMed PubMed Central
El Hout, M., Dos Santos, L., Hamaï, A., and Mehrpour, M. (2018). A promising new approach to cancer therapy: targeting iron metabolism in cancer stem cells. Semin. Cancer Biol. 53: 125–138, https://doi.org/10.1016/j.semcancer.2018.07.009.Search in Google Scholar PubMed
Foret, M.K., Lincoln, R., Do Carmo, S., Cuello, A.C., and Cosa, G. (2020). Connecting the “Dots”: from free radical lipid autoxidation to cell pathology and disease. Chem. Rev. 120: 12757–12787, https://doi.org/10.1021/acs.chemrev.0c00761.Search in Google Scholar PubMed
Friedmann Angeli, J.P., Schneider, M., Proneth, B., Tyurina, Y.Y., Tyurin, V.A., Hammond, V.J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al.. (2014). Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16: 1180–1191, https://doi.org/10.1038/ncb3064.Search in Google Scholar PubMed PubMed Central
Fukai, T. and Ushio-Fukai, M. (2011). Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid. Redox Signal. 15: 1583–1606, https://doi.org/10.1089/ars.2011.3999.Search in Google Scholar PubMed PubMed Central
Gazdar, A.F. (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 28: S24–S31, doi:https://doi.org/10.1038/onc.2009.198.Search in Google Scholar PubMed PubMed Central
Gorrini, C., Harris, I.S., and Mak, T.W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12: 931–947, https://doi.org/10.1038/nrd4002.Search in Google Scholar PubMed
Hambright, W.S., Fonseca, R.S., Chen, L., Na, R., and Ran, Q. (2017). Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 12: 8–17, https://doi.org/10.1016/j.redox.2017.01.021.Search in Google Scholar PubMed PubMed Central
Hangauer, M.J., Viswanathan, V.S., Ryan, M.J., Bole, D., Eaton, J.K., Matov, A., Galeas, J., Dhruv, H.D., Berens, M.E., Schreiber, S.L., et al.. (2017). Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551: 247–250, https://doi.org/10.1038/nature24297.Search in Google Scholar PubMed PubMed Central
Haslehurst, A.M., Koti, M., Dharsee, M., Nuin, P., Evans, K., Geraci, J., Childs, T., Chen, J., Li, J., Weberpals, J., et al.. (2012). EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12: 91, https://doi.org/10.1186/1471-2407-12-91.Search in Google Scholar PubMed PubMed Central
Herbst, R., Morgensztern, D., and Boshoff, C. (2018). The biology and management of non-small cell lung cancer. Nature 553: 446–454, https://doi.org/10.1038/nature25183.Search in Google Scholar PubMed
Herscovitch, M., Comb, W., Ennis, T., Coleman, K., Yong, S., Armstead, B., Kalaitzidis, D., Chandani, S., and Gilmore, T.D. (2008). Intermolecular disulfide bond formation in the NEMO dimer requires Cys54 and Cys347. Biochem. Biophys. Res. Commun. 367: 103–108, https://doi.org/10.1016/j.bbrc.2007.12.123.Search in Google Scholar PubMed PubMed Central
Hinman, A., Holst, C.R., Latham, J.C., Bruegger, J.J., Ulas, G., McCusker, K.P., Amagata, A., Davis, D., Hoff, K.G., Kahn-Kirby, A.H., et al.. (2018). Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One 13: e0201369, https://doi.org/10.1371/journal.pone.0201369.Search in Google Scholar PubMed PubMed Central
Hiom, S.C. (2015). Diagnosing cancer earlier: reviewing the evidence for improving cancer survival. Br. J. Cancer 112: S1–S5, doi:https://doi.org/10.1038/bjc.2015.23.Search in Google Scholar PubMed PubMed Central
Hirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., et al.. (2015). In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget 6: 38789–38803, https://doi.org/10.18632/oncotarget.5887.Search in Google Scholar PubMed PubMed Central
Ishikawa, F., Kaneko, E., Sugimoto, T., Ishijima, T., Wakamatsu, M., Yuasa, A., Sampei, R., Mori, K., Nose, K., and Shibanuma, M. (2014). A mitochondrial thioredoxin-sensitive mechanism regulates TGF-beta-mediated gene expression associated with epithelial-mesenchymal transition. Biochem. Biophys. Res. Commun. 443: 821–827, https://doi.org/10.1016/j.bbrc.2013.12.050.Search in Google Scholar PubMed
Jaffer, O.A., Carter, A.B., Sanders, P.N., Dibbern, M.E., Winters, C.J., Murthy, S., Ryan, A.J., Rokita, A.G., Prasad, A.M., Zabner, J., et al.. (2015). Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-beta-mediated collagen production in a murine asthma model. Am. J. Respir. Cell Mol. Biol. 52: 106–115, https://doi.org/10.1165/rcmb.2013-0519oc.Search in Google Scholar
Jiang, J., Wang, K., Chen, Y., Chen, H., Nice, E.C., and Huang, C. (2017). Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. Signal. Transduct. Target. Ther. 2: 17036, https://doi.org/10.1038/sigtrans.2017.36.Search in Google Scholar PubMed PubMed Central
Kagan, V.E., Mao, G., Qu, F., Angeli, J.P.F., Doll, S., Croix, C.S., Dar, H.H., Liu, B., Tyurin, V.A., Ritov, V.B., et al.. (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13: 81–90, https://doi.org/10.1038/nchembio.2238.Search in Google Scholar PubMed PubMed Central
Karar, J. and Maity, A. (2011). PI3K/AKT/mTOR pathway in angiogenesis. Front. Mol. Neurosci. 4: 51, https://doi.org/10.3389/fnmol.2011.00051.Search in Google Scholar PubMed PubMed Central
Karisch, R., Fernandez, M., Taylor, P., Virtanen, C., St-Germain, J.R., Jin, L.L., Harris, I.S., Mori, J., Mak, T.W., Senis, Y.A., et al.. (2011). Global proteomic assessment of the classical protein-tyrosine phosphatome and “Redoxome”. Cell 146: 826–840, https://doi.org/10.1016/j.cell.2011.07.020.Search in Google Scholar PubMed PubMed Central
Kempf, E., Rousseau, B., Besse, B., and Paz-Ares, L. (2016). KRAS oncogene in lung cancer: focus on molecularly driven clinical trials. Eur. Respir. Rev. 25: 71–76, https://doi.org/10.1183/16000617.0071-2015.Search in Google Scholar PubMed
Kim, J.H., Bogner, P.N., Baek, S.H., Ramnath, N., Liang, P., Kim, H.R., Andrews, C., and Park, Y.M. (2008). Up-regulation of peroxiredoxin 1 in lung cancer and its implication as a prognostic and therapeutic target. Clin. Cancer Res. 14: 2326–2333, https://doi.org/10.1158/1078-0432.ccr-07-4457.Search in Google Scholar PubMed
Kim, Y.J., Lee, W.S., Ip, C., Chae, H.Z., Park, E.M., and Park, Y.M. (2006). Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex. Cancer Res. 66: 7136–7142, https://doi.org/10.1158/0008-5472.can-05-4446.Search in Google Scholar
Kurrey, N.K., Jalgaonkar, S.P., Joglekar, A.V., Ghanate, A.D., Chaskar, P.D., Doiphode, R.Y., and Bapat, S.A. (2009). Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cell. 27: 2059–2068, https://doi.org/10.1002/stem.154.Search in Google Scholar PubMed
Kurutas, E.B. (2016). The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr. J. 15: 71, https://doi.org/10.1186/s12937-016-0186-5.Search in Google Scholar PubMed PubMed Central
Kwon, T., Rho, J.K., Lee, J.C., Park, Y.H., Shin, H.J., Cho, S., Kang, Y.K., Kim, B.Y., Yoon, D.Y., and Yu, D.Y. (2015). An important role for peroxiredoxin II in survival of A549 lung cancer cells resistant to gefitinib. Exp. Mol. Med. 47: e165, https://doi.org/10.1038/emm.2015.24.Search in Google Scholar PubMed PubMed Central
Labunskyy, V.M., Hatfield, D.L., and Gladyshev, V.N. (2014). Selenoproteins: molecular pathways and physiological roles. Physiol. Rev. 94: 739–777, https://doi.org/10.1152/physrev.00039.2013.Search in Google Scholar PubMed PubMed Central
Lamouille, S.X. and J. Derynck, R. (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15: 178–196, https://doi.org/10.1038/nrm3758.Search in Google Scholar PubMed PubMed Central
Lee, S.R., Yang, K.S., Kwon, J., Lee, C., Jeong, W., and Rhee, S.G. (2002). Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277: 20336–20342, https://doi.org/10.1074/jbc.m111899200.Search in Google Scholar
Leonetti, A., Sharma, S., Minari, R., Perego, P., Giovannetti, E., and Tiseo, M. (2019). Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 121: 725–737, https://doi.org/10.1038/s41416-019-0573-8.Search in Google Scholar PubMed PubMed Central
Li, J., Cao, F., Yin, H.-L., Huang, Z.-J., Lin, Z.-T., Mao, N., Sun, B., and Wang, G. (2020). Ferroptosis: past, present and future. Cell Death Dis. 11: 88, https://doi.org/10.1038/s41419-020-2298-2.Search in Google Scholar PubMed PubMed Central
Li, M.Y., Lai, P.L., Chou, Y.T., Chi, A.P., Mi, Y.Z., Khoo, K.H., Chang, G.D., Wu, C.W., Meng, T.C., and Chen, G.C. (2015a). Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation. Oncogene 34: 3791–3803, https://doi.org/10.1038/onc.2014.312.Search in Google Scholar PubMed
Li, R., Jia, Z., and Trush, M.A. (2016). Defining ROS in biology and medicine. React. Oxyg. Species (Apex) 1: 9–21, https://doi.org/10.20455/ros.2016.803.Search in Google Scholar PubMed PubMed Central
Li, W., Cao, L., Han, L., Xu, Q., and Ma, Q. (2015b). Superoxide dismutase promotes the epithelial-mesenchymal transition of pancreatic cancer cells via activation of the H2O2/ERK/NF-kappaB axis. Int. J. Oncol. 46: 2613–2620, https://doi.org/10.3892/ijo.2015.2938.Search in Google Scholar PubMed
Liao, B.-C., Griesing, S., and Yang, J.C.-H. (2019). Second-line treatment of EGFR T790M-negative non-small cell lung cancer patients. Ther. Adv. Med. Oncol. 11: 1–16, https://doi.org/10.1177/1758835919890286.Search in Google Scholar PubMed PubMed Central
Lim, S., Becker, A., Zimmer, A., Lu, J., Buettner, R., and Kirfel, J. (2013). SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. PLoS One 8: e66558, https://doi.org/10.1371/journal.pone.0066558.Search in Google Scholar PubMed PubMed Central
Liu, J., Kang, R., and Tang, D. (2021). The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther., https://doi.org/10.1038/s41417-021-00383-9.Search in Google Scholar PubMed
Liu, Y., Li, Q., Zhou, L., Xie, N., Nice, E.C., Zhang, H., Huang, C., and Lei, Y. (2016). Cancer drug resistance: redox resetting renders a way. Oncotarget 7: 42740–42761, https://doi.org/10.18632/oncotarget.8600.Search in Google Scholar PubMed PubMed Central
Liu, Y.R., Liang, L., Zhao, J.M., Zhang, Y., Zhang, M., Zhong, W.L., Zhang, Q., Wei, J.J., Li, M., Yuan, J., et al.. (2017). Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters. Oncotarget 8: 52901–52912, https://doi.org/10.18632/oncotarget.17548.Search in Google Scholar PubMed PubMed Central
Maiti, A.K. (2012). Genetic determinants of oxidative stress-mediated sensitization of drug-resistant cancer cells. Int. J. Cancer 130: 1–9, https://doi.org/10.1002/ijc.26306.Search in Google Scholar PubMed
Malouf, G.G., Taube, J.H., Lu, Y., Roysarkar, T., Panjarian, S., Estecio, M.R., Jelinek, J., Yamazaki, J., Raynal, N.J., Long, H., et al.. (2013). Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition. Genome Biol. 14: R144, https://doi.org/10.1186/gb-2013-14-12-r144.Search in Google Scholar PubMed PubMed Central
Miller, E.W., Tulyathan, O., Isacoff, E.Y., and Chang, C.J. (2007). Molecular imaging of hydrogen peroxide produced for cell signaling. Nat. Chem. Biol. 3: 263–267, https://doi.org/10.1038/nchembio871.Search in Google Scholar PubMed
Moreno, C. (2020). Standard treatment approaches for relapsed/refractory chronic lymphocytic leukemia after frontline chemoimmunotherapy. Hematology Am. Soc. Hematol. Educ. Program 2020: 33–40, https://doi.org/10.1182/hematology.2020000086.Search in Google Scholar PubMed PubMed Central
Naumov, G.N., Townson, J.L., MacDonald, I.C., Wilson, S.M., Bramwell, V.H., Groom, A.C., and Chambers, A.F. (2003). Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res. Treat. 82: 199–206, https://doi.org/10.1023/b:brea.0000004377.12288.3c.10.1023/B:BREA.0000004377.12288.3cSearch in Google Scholar
Neumann, J., Zeindl-Eberhart, E., Kirchner, T., and Jung, A. (2009). Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol. Res. Pract. 205: 858–862, https://doi.org/10.1016/j.prp.2009.07.010.Search in Google Scholar PubMed
Nicolussi, A., D’Inzeo, S., Capalbo, C., Giannini, G., and Coppa, A. (2017). The role of peroxiredoxins in cancer. Mol. Clin. Oncol. 6: 139–153, https://doi.org/10.3892/mco.2017.1129.Search in Google Scholar PubMed PubMed Central
Overstreet, J.M., Samarakoon, R., Meldrum, K.K., and Higgins, P.J. (2014). Redox control of p53 in the transcriptional regulation of TGF-beta1 target genes through SMAD cooperativity. Cell. Signal. 26: 1427–1436, https://doi.org/10.1016/j.cellsig.2014.02.017.Search in Google Scholar
Panieri, E. and Santoro, M.M. (2016). ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis. 7: e2253, https://doi.org/10.1038/cddis.2016.105.Search in Google Scholar
Park, K., Tan, E.-H., O’Byrne, K., Zhang, L., Boyer, M., Mok, T., Hirsh, V., Yang, J.C.-H., Lee, K.H., Lu, S., et al.. (2016). Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 17: 577–589, https://doi.org/10.1016/s1470-2045(16)30033-x.Search in Google Scholar
Park, M.W., Cha, H.W., Kim, J., Kim, J.H., Yang, H., Yoon, S., Boonpraman, N., Yi, S.S., Yoo, I.D., and Moon, J.S. (2021). NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol. 41: 101947, https://doi.org/10.1016/j.redox.2021.101947.Search in Google Scholar PubMed PubMed Central
Paulsen, C.E. and Carroll, K.S. (2013). Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery. Chem. Rev. 113: 4633–4679, https://doi.org/10.1021/cr300163e.Search in Google Scholar PubMed PubMed Central
Paulsen, C.E., Truong, T.H., Garcia, F.J., Homann, A., Gupta, V., Leonard, S.E., and Carroll, K.S. (2011). Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nat. Chem. Biol. 8: 57–64, https://doi.org/10.1038/nchembio.736.Search in Google Scholar PubMed PubMed Central
Phan, T.G. and Croucher, P.I. (2020). The dormant cancer cell life cycle. Nat. Rev. Cancer 20: 398–411, https://doi.org/10.1038/s41568-020-0263-0.Search in Google Scholar PubMed
Pinnix, Z.K., Miller, L.D., Wang, W., D’Agostino, R.Jr., Kute, T., Willingham, M.C., Hatcher, H., Tesfay, L., Sui, G., Di, X., et al.. (2010). Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2: 43ra56, https://doi.org/10.1126/scisignal.3001127.Search in Google Scholar
Pociask, D.A., Sime, P.J., and Brody, A.R. (2004). Asbestos-derived reactive oxygen species activate TGF-beta1. Lab. Invest. 84: 1013–1023, https://doi.org/10.1038/labinvest.3700109.Search in Google Scholar PubMed
Polyak, K. and Weinberg, R.A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9: 265–273, https://doi.org/10.1038/nrc2620.Search in Google Scholar PubMed
Qin, S., Jiang, J., Lu, Y., Nice, E.C., Huang, C., Zhang, J., and He, W. (2020). Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct. Target. Ther. 5: 228, https://doi.org/10.1038/s41392-020-00313-5.Search in Google Scholar PubMed PubMed Central
Reth, M. (2002). Hydrogen peroxide as second messenger in lymphocyte activation. Nat. Immunol. 3: 1129–1134, https://doi.org/10.1038/ni1202-1129.Search in Google Scholar PubMed
Russo, A., Franchina, T., Rita Ricciardi, G.R., Picone, A., Ferraro, G., Zanghì, M., Toscano, G., Giordano, A., and Adamo, V. (2015). A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): old successes and future perspectives. Oncotarget 6: 26814–26825, https://doi.org/10.18632/oncotarget.4254.Search in Google Scholar PubMed PubMed Central
Ryter, S.W., Kim, H.P., Hoetzel, A., Park, J.W., Nakahira, K., Wang, X., and Choi, A.M. (2007). Mechanisms of cell death in oxidative stress. Antioxid. Redox Signal. 9: 49–89, https://doi.org/10.1089/ars.2007.9.49.Search in Google Scholar PubMed
Saxena, M., Stephens, M.A., Pathak, H., and Rangarajan, A. (2011). Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis. 2: e179, https://doi.org/10.1038/cddis.2011.61.Search in Google Scholar PubMed PubMed Central
Schieber, M. and Chandel, N.S. (2014). ROS function in redox signaling and oxidative stress. Curr. Biol. 24: R453–R462, https://doi.org/10.1016/j.cub.2014.03.034.Search in Google Scholar PubMed PubMed Central
Sever, R. and Brugge, J.S. (2015). Signal transduction in cancer. Cold Spring Harb. Perspect. Med. 5, https://doi.org/10.1101/cshperspect.a006098.Search in Google Scholar PubMed PubMed Central
Shan, Z., Wei, Z., and Shaikh, Z.A. (2018). Suppression of ferroportin expression by cadmium stimulates proliferation, EMT, and migration in triple-negative breast cancer cells. Toxicol. Appl. Pharmacol. 356: 36–43, https://doi.org/10.1016/j.taap.2018.07.017.Search in Google Scholar PubMed PubMed Central
Shvedova, A.A., Kisin, E.R., Murray, A.R., Kommineni, C., Castranova, V., Fadeel, B., and Kagan, V.E. (2008). Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes. Toxicol. Appl. Pharmacol. 231: 235–240, https://doi.org/10.1016/j.taap.2008.04.018.Search in Google Scholar PubMed
Skrypek, N., Goossens, S., De Smedt, E., Vandamme, N., and Berx, G. (2017). Epithelial-to-mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genet. 33: 943–959, https://doi.org/10.1016/j.tig.2017.08.004.Search in Google Scholar PubMed
Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K.H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., et al.. (2018). Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378: 113–125, https://doi.org/10.1056/nejmoa1713137.Search in Google Scholar PubMed
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71: 209–249, https://doi.org/10.3322/caac.21660.Search in Google Scholar PubMed
Talukdar, S., Bhoopathi, P., Emdad, L., Das, S., Sarkar, D., and Fisher, P.B. (2019). Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Adv. Cancer Res. 141: 43–84, https://doi.org/10.1016/bs.acr.2018.12.002.Search in Google Scholar PubMed
Tam, W.L. and Weinberg, R.A. (2013). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19: 1438–1449, https://doi.org/10.1038/nm.3336.Search in Google Scholar PubMed PubMed Central
Tonks, N.K. (2005). Redox redux: revisiting PTPs and the control of cell signaling. Cell 121: 667–670, https://doi.org/10.1016/j.cell.2005.05.016.Search in Google Scholar PubMed
Truong, T.H., Ung, P.M., Palde, P.B., Paulsen, C.E., Schlessinger, A., and Carroll, K.S. (2016). Molecular basis for redox activation of epidermal growth factor receptor kinase. Cell Chem. Biol. 23: 837–848, https://doi.org/10.1016/j.chembiol.2016.05.017.Search in Google Scholar PubMed PubMed Central
Tumbrink, H.L., Heimsoeth, A., and Sos, M.L. (2021). The next tier of EGFR resistance mutations in lung cancer. Oncogene 40: 1–11, https://doi.org/10.1038/s41388-020-01510-w.Search in Google Scholar PubMed
Waters, A.M. and Der, C.J. (2018). KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med. 8, https://doi.org/10.1101/cshperspect.a031435.Search in Google Scholar PubMed PubMed Central
Wee, P. and Wang, Z. (2017). Epidermal growth factor receptor cell proliferation signaling pathways. Cancers 9, https://doi.org/10.3390/cancers9050052.Search in Google Scholar PubMed PubMed Central
Weidemann, A. and Johnson, R.S. (2008). Biology of HIF-1alpha. Cell Death Differ. 15: 621–627, https://doi.org/10.1038/cdd.2008.12.Search in Google Scholar PubMed
Weidenfeld, K. and Barkan, D. (2018). EMT and stemness in tumor dormancy and outgrowth: are they intertwined processes? Front. Oncol. 8: 381, https://doi.org/10.3389/fonc.2018.00381.Search in Google Scholar PubMed PubMed Central
Wong, H.S., Dighe, P.A., Mezera, V., Monternier, P.A., and Brand, M.D. (2017). Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions. J. Biol. Chem. 292: 16804–16809, https://doi.org/10.1074/jbc.r117.789271.Search in Google Scholar PubMed PubMed Central
Woyach, J.A., Bojnik, E., Ruppert, A.S., Stefanovski, M.R., Goettl, V.M., Smucker, K.A., Smith, L.L., Dubovsky, J.A., Towns, W.H., MacMurray, J., et al.. (2014). Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 123: 1207–1213, https://doi.org/10.1182/blood-2013-07-515361.Search in Google Scholar PubMed PubMed Central
Wu, J., Liu, C., Tsui, S.T., and Liu, D. (2016a). Second-generation inhibitors of Bruton tyrosine kinase. J. Hematol. Oncol. 9: 80, https://doi.org/10.1186/s13045-016-0313-y.Search in Google Scholar PubMed PubMed Central
Wu, J., Zhang, M., and Liu, D. (2016b). Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J. Hematol. Oncol. 9: 21, https://doi.org/10.1186/s13045-016-0250-9.Search in Google Scholar PubMed PubMed Central
Yang, J.C., Hirsh, V., Schuler, M., Yamamoto, N., O’Byrne, K.J., Mok, T.S., Zazulina, V., Shahidi, M., Lungershausen, J., Massey, D., et al.. (2013). Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31: 3342–3350, https://doi.org/10.1200/jco.2012.46.1764.Search in Google Scholar PubMed
Yang, W.S. and Stockwell, B.R. (2008). Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15: 234–245, https://doi.org/10.1016/j.chembiol.2008.02.010.Search in Google Scholar PubMed PubMed Central
Yao, D., Dai, C., and Peng, S. (2011). Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9: 1608–1620, https://doi.org/10.1158/1541-7786.mcr-10-0568.Search in Google Scholar
Zhang, K.-H., Tian, H.-Y., Gao, X., Lei, W.-W., Hu, Y., Wang, D.-M., Pan, X.-C., Yu, M.-L., Xu, G.-J., Zhao, F.-K., et al.. (2009). Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. Cancer Res. 69: 5340–5348, https://doi.org/10.1158/0008-5472.can-09-0112.Search in Google Scholar
Zhang, W., Trachootham, D., Liu, J., Chen, G., Pelicano, H., Garcia-Prieto, C., Lu, W., Burger, J.A., Croce, C.M., Plunkett, W., et al.. (2012). Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat. Cell Biol. 14: 276–286, https://doi.org/10.1038/ncb2432.Search in Google Scholar PubMed PubMed Central
Zhitomirsky, B. and Assaraf, Y.G. (2016). Lysosomes as mediators of drug resistance in cancer. Drug Resist. Updat. 24: 23–33, https://doi.org/10.1016/j.drup.2015.11.004.Search in Google Scholar PubMed
Zhong, L., Li, Y., Xiong, L., Wang, W., Wu, M., Yuan, T., Yang, W., Tian, C., Miao, Z., Wang, T., et al.. (2021). Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct. Target. Ther. 6: 201, https://doi.org/10.1038/s41392-021-00572-w.Search in Google Scholar PubMed PubMed Central
Zhu, X., Chen, L., Liu, L., and Niu, X. (2019). EMT-mediated acquired EGFR-TKI resistance in NSCLC: mechanisms and strategies. Front. Oncol. 9: 1044, https://doi.org/10.3389/fonc.2019.01044.Search in Google Scholar PubMed PubMed Central
© 2021 Walter de Gruyter GmbH, Berlin/Boston
