In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer
Open accessAbstract
In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.
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Median survival almost doubled in the paper's models and increased by 2-3 weeks, double the increase induced by sorafenib in comparable models.
“Strikingly, median survival almost doubled in our models and increased by 2–3 weeks, double the increase induced by the kinase inhibitor sorafenib, a standard of care in unresectable HCC, in comparable models62.”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [62]
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Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097 · see citing works
Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,606 · see citing works
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
Signal integration by JNK and p38 MAPK pathways in cancer development
Wagner, E. F., & Nebreda, Á. R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2694 · Cited by 2,583 · see citing works
Discovery and development of sorafenib: a multikinase inhibitor for treating cancer
Wilhelm, S. M., Carter, C., Lynch, M. J., Lowinger, T. B., Dumas, J., Smith, R. A., Schwartz, B. E., Simantov, R., & Kelley, S. L. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2130 · Cited by 1,826 · see citing works
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · see citing works
Self-citationGuichard, C., Amaddeo, G., Imbeaud, S., Ladeiro, Y., Pelletier, L., Benmaad, I., Caldéraro, J., Bioulac‐Sage, P., Letexier, M., Degos, F., et al. (2012) · Nature Genetics · doi:10.1038/ng.2256 · Cited by 1,451 · see citing works
Hepatocellular carcinoma: clinical frontiers and perspectives
Bruix, J., Gores, G. J., & Mazzaferro, V. (2014) · Gut · doi:10.1136/gutjnl-2013-306627 · Cited by 1,367 · see citing works
T-helper-1-cell cytokines drive cancer into senescence
Braumüller, H., Wieder, T., Brenner, E., Aßmann, S., Hahn, M., Alkhaled, M., Schilbach, K., Essmann, F., Kneilling, M., Griessinger, C., et al. (2013) · Nature · doi:10.1038/nature11824 · Cited by 720 · see citing works
Self-citationUbiquitous Activation of Ras and Jak/Stat Pathways in Human HCC
Calvisi, D. F., Ladu, S., Gorden, A., Farina, M., Conner, E. A., Lee, J., Factor, V. M., & Thorgeirsson, S. S. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.01.006 · Cited by 710 · see citing works
JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis
Steelman, L. S., Pohnert, S. C., Shelton, J. G., Franklin, R. A., Bertrand, F. E., & McCubrey, J. A. (2004) · Leukemia · doi:10.1038/sj.leu.2403241 · Cited by 681 · see citing works
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577 · see citing works
p38 MAP kinases: beyond the stress response
Nebreda, Á. R., & Porrás, A. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01595-4 · Cited by 552 · see citing works
Sawey, E. T., Chanrion, M., Cai, C., Wu, G., Zhang, J., Zender, L., Zhao, A. S., Busuttil, R. W., Yee, H. T., Stein, L. D., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.040 · Cited by 437 · see citing works
Self-citationMED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling
Huang, S., Hölzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., Garnett, M., Grernrum, W., Sun, C., Prahallad, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.035 · Cited by 430 · see citing works
Design of a genome-wide siRNA library using an artificial neural network
Huesken, D., Lange, J., Mickanin, C., Weiler, J., Asselbergs, F., Warner, J., Meloon, B., Engel, S., Rosenberg, A. Z., Cohen, D., et al. (2005) · Nature Biotechnology · doi:10.1038/nbt1118 · Cited by 387 · see citing works
Swanton, C., Marani, M., Pardo, O. E., Warne, P. H., Kelly, G. P., Sahai, E. A., Elustondo, F., Chang, J. C., Temple, J., Ahmed, A. A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.011 · Cited by 381 · see citing works
A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor
Turner, N. C., Lord, C. J., Iorns, E. J., Brough, R., Swift, S., Elliott, R. J. R., Rayter, S., Tutt, A. N. J., & Ashworth, A. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.61 · Cited by 322 · see citing works
Topoisomerase levels determine chemotherapy response in vitro and in vivo
Burgess, D. J., Doles, J. D., Zender, L., Xue, W., Ma, B., McCombie, W. R., Hannon, G. J., Lowe, S. W., & Hemann, M. T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803513105 · Cited by 302 · see citing works
Self-citationMutant BRAF Melanomas—Dependence and Resistance
Poulikakos, P. I., & Rosen, N. X. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.008 · Cited by 248 · see citing works
Etiology-dependent molecular mechanisms in human hepatocarcinogenesis
Schlaeger, C., Longerich, T., Schíller, C., Bewerunge, P., Mehrabi, A., Toedt, G., Kleeff, J. H., Ehemann, V., Eils, R., Lichter, P., et al. (2007) · Hepatology · doi:10.1002/hep.22033 · Cited by 203 · see citing works
Self-citationSelective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory Disorders
GOLDSTEIN, D. M., Kuglstatter, A., Lou, Y. C., & Soth, M. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm9012906 · Cited by 180 · see citing works
p38 MAP kinase inhibitors: many are made, but few are chosen.
Dominguez, C., Powers, D. A., & Tamayo, N. A. (2005) · PubMed · Cited by 166 · see citing works
Novel strategies for inhibition of the p38 MAPK pathway
ZHANG, J., SHEN, B., & Lin, A. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.04.008 · Cited by 162 · see citing works
Calvisi, D. F., Ladu, S., Conner, E. A., Seo, D., Hsieh, J., Factor, V. M., & Thorgeirsson, S. S. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.06.036 · Cited by 160 · see citing works
A pipeline for the generation of shRNA transgenic mice
Dow, L. E., Premsrirut, P. K., Zuber, J., Fellmann, C., McJunkin, K., Miething, C., Park, Y., Dickins, R. A., Hannon, G. J., & Lowe, S. W. (2012) · Nature Protocols · doi:10.1038/nprot.2011.446 · Cited by 159 · see citing works
Self-citationA Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration
Wuestefeld, T., Pesic, M., Rudalska, R., Dauch, D., Longerich, T., Kang, T.-W., Yevsa, T., Heinzmann, F., Hoenicke, L., Hohmeyer, A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.026 · Cited by 149 · see citing works
Self-citationHindley, A. D., & Kölch, W. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.8.1575 · Cited by 147 · see citing works
MacNee, W., Allan, R., Jones, I., Salvo, M. C. D., & Tan, L. F. (2013) · Thorax · doi:10.1136/thoraxjnl-2012-202744 · Cited by 139 · see citing works
Carlson, C. M., Frandsen, J. L., Kirchhof, N., McIvor, R. S., & Largaespada, D. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502974102 · Cited by 134 · see citing works
Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor
Koeberle, S. C., Romir, J., Fischer, S., Koeberle, A., Schattel, V., Albrecht, W., Grütter, C., Werz, O., Rauh, D., Stehle, T., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.761 · Cited by 123 · see citing works
Self-citationGiroux, V., Iovanna, J., & Dagorn, J. (2006) · The FASEB Journal · doi:10.1096/fj.06-6239com · Cited by 90 · see citing works
Hepatocellular carcinoma and sorafenib: too many resistance mechanisms?
Berasain, C. (2013) · Gut · doi:10.1136/gutjnl-2013-304564 · Cited by 89 · see citing works
Resistance to RAF Inhibitors Revisited
Hartsough, E. J., Shao, Y., & Aplin, A. E. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.358 · Cited by 75 · see citing works
Evolution of systemic therapy of advanced hepatocellular carcinoma
Yau, T. C. C., Chan, P., Epstein, R. J., & Poon, R. T. P. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.6437 · Cited by 67 · see citing works
Hope, H. R., Anderson, G. D., Burnette, B., Compton, R. P., Devraj, R. V., Hirsch, J. L., Keith, R. H., Li, X., Mbalaviele, G., Messing, D., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.158329 · Cited by 61 · see citing works
Are MAP Kinases Drug Targets? Yes, but Difficult Ones
Margutti, S., & Laufer, S. (2007) · ChemMedChem · doi:10.1002/cmdc.200600271 · Cited by 44 · see citing works
Self-citationFischer, S., Wentsch, H. K., Mayer‐Wrangowski, S. C., Zimmermann, M. O., Bauer, S. M., Storch, K., Nieß, R., Koeberle, S. C., Grütter, C., Boeckler, F. M., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301539x · Cited by 36 · see citing works
Self-citationLord, R., Suddle, A. R., & Ross, P. J. (2011) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2010.02545.x · Cited by 27 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Llovet, J. M., Kelley, R. K., Villanueva, A., Singal, A. G., Pikarsky, E., Roayaie, S., Lencioni, R., Koike, K., Zucman-Rossi, J., & Finn, R. S. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-00240-3 · Cited by 7,055 · see citing works
Llovet, J. M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., & Gores, G. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.18 · Cited by 2,531 · see citing works
NASH limits anti-tumour surveillance in immunotherapy-treated HCC
Pfister, D., Núñez, N. G., Pinyol, R., Govaere, O., Pinter, M., Szydlowska, M., Gupta, R., Qiu, M., Deczkowska, A., Weiner, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03362-0 · Cited by 1,294 · see citing works
Self-citationHigh-throughput functional genomics using CRISPR-Cas9
Shalem, O., Sanjana, N. E., & Zhang, F. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3899 · Cited by 1,233 · see citing works
Compromised MAPK signaling in human diseases: an update
Kim, E., & Choi, E. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1472-2 · Cited by 1,017 · see citing works
Diversity and versatility of p38 kinase signalling in health and disease
Canovas, B., & Nebreda, A. R. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00322-w · Cited by 657 · see citing works
Advances in targeted therapies for hepatocellular carcinoma in the genomic era
Llovet, J. M., Villanueva, A., Lachenmayer, A., & Finn, R. S. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.103 · Cited by 619 · see citing works
Advances in molecular classification and precision oncology in hepatocellular carcinoma
Rebouissou, S., & Nault, J. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.017 · Cited by 580 · see citing works
Genetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
Hepatic fibrosis 2022: Unmet needs and a blueprint for the future
Friedman, S. L., & Pinzani, M. (2022) · Hepatology · doi:10.1002/hep.32285 · Cited by 430 · see citing works
Wei, L., Lee, D., Law, C.-T., Zhang, M. S., Shen, J., Chin, D. W.-C., Zhang, A., Tsang, F. H.-C., Wong, C. L.-S., Ng, I. O.-L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12606-7 · Cited by 428 · see citing works
Cardiac glycosides are broad-spectrum senolytics
Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0122-z · Cited by 359 · see citing works
Self-citationDauch, D., Rudalska, R., Cossa, G., Nault, J., Kang, T.-W., Wüestefeld, T., Hohmeyer, A., Imbeaud, S., Yevsa, T., Hoenicke, L., et al. (2016) · Nature Medicine · doi:10.1038/nm.4107 · Cited by 274 · see citing works
Self-citationConche, C., Finkelmeier, F., Pesic, M. H., Nicolas, A. M., Böttger, T. W., Kennel, K. B., Denk, D., Ceteci, F., Mohs, K., Engel, E., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-327909 · Cited by 267 · see citing works
Self-citationTargeted therapy for hepatocellular carcinoma: Challenges and opportunities
Chen, S., Cao, Q., Wen, W., & Wang, H. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.114428 · Cited by 253 · see citing works
Chen, J., Jin, R., Zhao, J., Liu, J., Ying, H., Yan, H., Zhou, S., Liang, Y., Huang, D., Liang, X. H., et al. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.06.019 · Cited by 252 · see citing works
Tovar, V., Cornellà, H., Moeini, A., Vidal, S. J., Hoshida, Y., Sia, D., Peix, J., Cabellos, L., Alsinet, C., Torrecilla, S., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309501 · Cited by 206 · see citing works
Corre, I., Paris, F., & Huot, J. (2017) · Oncotarget · doi:10.18632/oncotarget.18264 · Cited by 195 · see citing works
The Stress Kinase p38α as a Target for Cancer Therapy
Igea, A., & Nebreda, Á. R. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0173 · Cited by 190 · see citing works
Xu, Y., Huang, J., Ma, L., Shan, J., Shen, J., Yang, Z., Liu, L., Luo, Y., Yao, C., & Qian, C. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.11.034 · Cited by 165 · see citing works
ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease
Watson, G. W., Ronai, Z. A., & Lau, E. K. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.02.004 · Cited by 154 · see citing works
Fang, J., Xu, L., Shang, L., Pan, C., Ding, J., Tang, Y., Liu, H., Liu, C.-X., Zheng, J., Zhang, Y., et al. (2018) · Hepatology · doi:10.1002/hep.30366 · Cited by 146 · see citing works
Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer
Zou, P., Xia, Y., Ji, J., Chen, W., Zhang, J., Chen, X., Rajamanickam, V., Chen, G., Wang, Z., Chen, L., et al. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.02.058 · Cited by 139 · see citing works
Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma
Ferrín, G., Misas, M. G., Amado, V., Rodríguez‐Perálvarez, M., & de la Mata, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041266 · Cited by 137 · see citing works
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges
Liu, X., & Qin, S. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-io-s1-s01 · Cited by 132 · see citing works
Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer
Genovese, G., Carugo, A., Tepper, J., Robinson, F. S., Li, L., Svelto, M., Nezi, L., Corti, D., Minelli, R., Pettazzoni, P., et al. (2017) · Nature · doi:10.1038/nature21064 · Cited by 131 · see citing works
Zheng, C., Zhang, B., Li, Y., Liu, K., Wei, W., Liang, S., Guo, H., Ma, K., Liu, Y., Wang, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202206798 · Cited by 130 · see citing works
Martinez-Quetglas, I., Pinyol, R., Dauch, D., Torrecilla, S., Tovar, V., Moeini, A., Alsinet, C., Portela, A., Rodríguez‐Carunchio, L., Solé, M., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.09.001 · Cited by 130 · see citing works
Self-citationEfficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib
Tong, M., Che, N., Zhou, L., Luk, S. T.-C., Kau, P. W., Chai, S., Ngan, E., Lo, C. M., Man, K., Ding, J., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.05.034 · Cited by 126 · see citing works
Song, C., Li, Y., Mou, H., Moore, J. E., Park, A., Pomyen, Y., Hough, S. H., Kennedy, Z., Fischer, A. H., Yin, H., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.12.002 · Cited by 120 · see citing works
Self-citationCurrent status and future prospects of p38α/MAPK14 kinase and its inhibitors
Madkour, M. M., Anbar, H. S., & El–Gamal, M. I. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113216 · Cited by 122 · see citing works
Molecular Pathogenesis of Hepatocellular Carcinoma
Ho, D., Lo, R., Chan, L., & Ng, I. (2016) · Liver Cancer · doi:10.1159/000449340 · Cited by 185 · see citing works
Chen, J., Xia, H., Zhang, X., Sekar, K., Seshachalam, V. P., Ooi, L. L., Hong, W., & Hui, K. M. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.01.014 · Cited by 118 · see citing works
McComb, S., Aguadé-Gorgorió, J., Behrmann, L., Marovca, B., Cario, G., Eckert, C., Schrappe, M., Stanulla, M., von Stackelberg, A., Bourquin, J., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad2986 · Cited by 113 · see citing works
The role of molecular enrichment on future therapies in hepatocellular carcinoma
Nault, J., Galle, P. R., & Marquardt, J. U. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.02.016 · Cited by 117 · see citing works
Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases
Liepelt, A., & Tacke, F. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00193.2016 · Cited by 108 · see citing works
Wang, C., Wang, H., Lieftink, C., du Chatinier, A., Gao, D., Jin, G., Jin, H., Beijersbergen, R. L., Qin, W., & Bernards, R. (2020) · Gut · doi:10.1136/gutjnl-2019-318506 · Cited by 107 · see citing works
The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer
García-Hernández, L., García‐Ortega, M. B., Ruiz-Alcalá, G., Carrillo, E., Marchal, J. A., & García, M. Á. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010370 · Cited by 106 · see citing works
Chang, L., Wang, G., Jia, T., Zhang, L., Li, Y., Han, Y., Zhang, K., Lin, G., Zhang, R., Li, J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8115 · Cited by 99 · see citing works
Wang, C., Jin, H., Gao, D., Lieftink, C., Evers, B., Jin, G., Zheng, X., Wang, L., Beijersbergen, R. L., Qin, W., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.07.004 · Cited by 93 · see citing works
Xu, X., Li, Y., Wu, Y., Wang, M., Lu, Y., Fang, Z., Wang, H., & Li, Y. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102564 · Cited by 92 · see citing works
Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma
Liu, J., Liu, Y., Meng, L., Liu, K., & Ji, B. (2017) · Oncology Reports · doi:10.3892/or.2017.5722 · Cited by 91 · see citing works
Hoffmann, K., Ganten, T. M., Gotthardtp, D., Radeleff, B. A., Settmacher, U., Kollmar, O., Nadalin, S., Karapanagiotou‐Schenkel, I., Kalle, C. V., Jäger, D., et al. (2015) · BMC Cancer · doi:10.1186/s12885-015-1373-z · Cited by 84 · see citing works
Wang, H., Ellipilli, S., Lee, W.-J., Li, X., Vieweger, M., Ho, Y., & Guo, P. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.12.007 · Cited by 83 · see citing works
Chen, Y., Liu, Y.-C., Sung, Y., Ramjiawan, R. R., Lin, T.-T., Chang, C.-C., Jeng, K., Chang, C.-F., Liu, C.-H., Gao, D.-Y., et al. (2017) · Scientific Reports · doi:10.1038/srep44123 · Cited by 81 · see citing works
Roy, S., Hooiveld, G., Seehawer, M., Caruso, S., Heinzmann, F., Schneider, A., Frank, A., Cardenas, D. V., Sonntag, R., Luedde, M., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.08.032 · Cited by 82 · see citing works
Self-citationBuczak, K., Ori, A., Kirkpatrick, J. M., Hölzer, K., Dauch, D., Roessler, S. K., Endris, V., Lasitschka, F., Parca, L., Schmidt, A., et al. (2018) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000189 · Cited by 79 · see citing works
Self-citationReyes, R., Wani, N. A., Ghoshal, K., Jacob, S. T., & Motiwala, T. (2016) · Gene Expression · doi:10.3727/105221616x693855 · Cited by 78 · see citing works
Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma
Nishida, N., Kitano, M., Sakurai, T., & Kudo, M. (2015) · Digestive Diseases · doi:10.1159/000439102 · Cited by 77 · see citing works
Modelling liver cancer microenvironment using a novel 3D culture system
Hrout, A. A., Cervantes-Gracia, K., Chahwan, R., & Amin, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-11641-7 · Cited by 74 · see citing works
Wang, K., Kievit, F. M., Sham, J. G., Jeon, M., Stephen, Z. R., Bakthavatsalam, A., Park, J. O., & Zhang, M. (2015) · Small · doi:10.1002/smll.201501985 · Cited by 74 · see citing works
Fornari, F., Giovannini, C., Piscaglia, F., & Gramantieri, L. (2021) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s285726 · Cited by 69 · see citing works
Song, Z., Liu, T., Chen, J., Ge, C., Zhao, F., Zhu, M., Chen, T., Cui, Y., Tian, H., Yao, M., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.06.016 · Cited by 69 · see citing works
Immune checkpoint blockade for the treatment of human hepatocellular carcinoma
Nishida, N., & Kudo, M. (2018) · Hepatology Research · doi:10.1111/hepr.13191 · Cited by 67 · see citing works
First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure
Zwirner, S., Abu Rmilah, A. A., Klotz, S., Pfaffenroth, B., Kloevekorn, P., Moschopoulou, A. A., Schuette, S., Haag, M., Selig, R., Li, K., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.023 · Cited by 65 · see citing works
“37,38 Nevertheless, to deeper characterize this phenomenon, we took advantage of two well-established murine liver carcinoma cell lines (Nras G12V Cdkn2a ARF−/− HCC cells 39,40 ; Nras G12V Trp53 −/− HCC cells 40 ).”
Self-citationYu, X., Tang, W., Yang, Y., Tang, L. P., Dai, R., Pu, B., Feng, C., & Xia, J. (2018) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2018.02.027 · Cited by 66 · see citing works
Xu, J., Liang, J., Meng, Y.-M., Yan, J., Yu, X.-J., Liu, C., Xu, L., Zhuang, S., & Zheng, L. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2131 · Cited by 63 · see citing works
PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling
Thürmer, M., Gollowitzer, A., Pein, H., Neukirch, K., Gelmez, E., Waltl, L., Wielsch, N., Winkler, R., Loeser, K., Grander, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30374-9 · Cited by 62 · see citing works
Hong, M., Almutairi, M. M., Li, S., & Li, J. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153174 · Cited by 62 · see citing works
Daudigeos‐Dubus, E., Dret, L. L., Lanvers‐Kaminsky, C., Bawa, O., Opolon, P., Vievard, A., Villa, I., Pagès, M., Bosq, J., Vassal, G., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142612 · Cited by 61 · see citing works
In vivo functional screening for systems-level integrative cancer genomics
Weber, J., Braun, C. J., Saur, D., & Rad, R. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0275-9 · Cited by 57 · see citing works
Nishida, N., Arizumi, T., Hagiwara, S., Ida, H., Sakurai, T., & Kudo, M. (2016) · Liver Cancer · doi:10.1159/000449475 · Cited by 60 · see citing works
Xu, Y., Xu, H., Li, M., Wu, H., Guo, Y., Chen, J., Shan, J., Chen, X., Shen, J., Ma, Q., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.03.049 · Cited by 60 · see citing works
Zhang, N., Wu, Y., Lyu, X., Li, B., Yan, X., Xiong, H., Li, X., Huang, G., Zeng, Y., Zhang, Y., et al. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.08.039 · Cited by 59 · see citing works
Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine
Kishikawa, T., Otsuka, M., Tan, P. S., Ohno, M., Sun, X., Yoshikawa, T., Shibata, C., Takata, A., Kojima, K., Takehana, K., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3234 · Cited by 59 · see citing works
Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib
Gotink, K. J., Rovithi, M. N., de Haas, R. R., Honeywell, R. J., Dekker, H., Poel, D., Azijli, K., Peters, G. J., Broxterman, H. J., & Verheul, H. M. W. (2015) · Cellular Oncology · doi:10.1007/s13402-015-0218-8 · Cited by 59 · see citing works
Ardelt, M. A., Fröhlich, T., Martini, E., Müller, M. J., Kanitz, V., Atzberger, C., Huber‐Cantonati, P., Meßner, M., Posselt, L., Lehr, T., et al. (2018) · Hepatology · doi:10.1002/hep.30190 · Cited by 58 · see citing works
LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer
Rudalska, R., Harbig, J., Snaebjornsson, M. T., Klotz, S., Zwirner, S., Taranets, L., Heinzmann, F., Kronenberger, T., Förster, M., Cui, W., et al. (2021) · Nature Cancer · doi:10.1038/s43018-020-00168-3 · Cited by 59 · see citing works
Self-citationExploring liver cancer biology through functional genetic screens
Wang, C., Cao, Y., Yang, C. G., Bernards, R., & Qin, W. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00465-x · Cited by 58 · see citing works
Negri, F., Bello, B. D., Porta, C., Campanini, N., Rossi, S. M., Tinelli, C., Poggi, G., Missale, G., Fanello, S., Salvagni, S., et al. (2015) · Liver International · doi:10.1111/liv.12778 · Cited by 56 · see citing works
Li, R., Gu, Y.-J., He, W., Yue, W., Jianhua, H., Huachuan, Z., Su, R., & Zhidong, L. (2017) · Oncotarget · doi:10.18632/oncotarget.15223 · Cited by 55 · see citing works
Towards quantitative and multiplexed in vivo functional cancer genomics
Winters, I. P., Murray, C. W., & Winslow, M. M. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0053-7 · Cited by 53 · see citing works
Synthetic Lethality in Cancer Therapeutics
Beijersbergen, R. L., Wessels, L. F. A., & Bernards, R. (2016) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-042016-073434 · Cited by 53 · see citing works
Xie, J., Lu, Y., Yu, B., Wu, J., & Liu, J. (2019) · Chinese Chemical Letters · doi:10.1016/j.cclet.2019.10.030 · Cited by 52 · see citing works
Opportunities and challenges provided by crosstalk between signalling pathways in cancer
Prahallad, A., & Bernards, R. (2015) · Oncogene · doi:10.1038/onc.2015.151 · Cited by 48 · see citing works
Xu, Z., Hu, J., Cao, H., Pilo, M. G., Cigliano, A., Shao, Z., Xu, M. M., Ribback, S., Dombrowski, F., Calvisi, D. F., et al. (2018) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.158 · Cited by 49 · see citing works
Dietrich, P., Gaza, A., Wormser, L., FRITZ, V. K., Hellerbrand, C., & Bosserhoff, A. (2019) · Neoplasia · doi:10.1016/j.neo.2018.11.011 · Cited by 49 · see citing works
c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases
Rehfeldt, S. C. H., Majolo, F., Goettert, M. I., & Laufer, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249677 · Cited by 46 · see citing works
Self-citationChen, Y., Zhao, D., Xiao, F., Li, X., Li, J., Su, Z., & Jiang, X. (2023) · Advanced Materials · doi:10.1002/adma.202209672 · Cited by 47 · see citing works
p38MAPK and Chemotherapy: We Always Need to Hear Both Sides of the Story
García‐Cano, J., Roche, O., Cimas, F. J., Pascual‐Serra, R., Ortega‐Muelas, M., Fernández‐Aroca, D. M., & Sánchez‐Prieto, R. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00069 · Cited by 47 · see citing works
Combination treatment including targeted therapy for advanced hepatocellular carcinoma
Lin, J., Wu, L., Bai, X., Xie, Y., Wang, A., Zhang, H., Yang, X., Wan, X., Lu, X., Sang, X., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11954 · Cited by 47 · see citing works
Yeddula, N., Xia, Y., Ke, E., Beumer, J., & Verma, I. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520110112 · Cited by 44 · see citing works
Ohata, Y., Shimada, S., Akiyama, Y., Mogushi, K., Nakao, K., Matsumura, S., Aihara, A., Mitsunori, Y., Ban, D., Ochiai, T., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0728 · Cited by 44 · see citing works
Stress kinases in the development of liver steatosis and hepatocellular carcinoma
Cicuéndez, B., Ruiz-Garrido, I., Mora, A., & Sabio, G. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101190 · Cited by 45 · see citing works
Hajiasgharzadeh, K., Somi, M. H., Shanehbandi, D., Mokhtarzadeh, A., & Baradaran, B. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27015 · Cited by 43 · see citing works
New tools for old drugs: Functional genetic screens to optimize current chemotherapy
Gerhards, N. M., & Rottenberg, S. (2018) · Drug Resistance Updates · doi:10.1016/j.drup.2018.01.001 · Cited by 42 · see citing works
Yoo, J., Yu, S. J., Na, J., Kim, K., Cho, Y. Y., Lee, Y. B., Cho, E. J., Lee, J., Kim, Y. J., Youn, H., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061292 · Cited by 42 · see citing works
Shao, Y. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i36.10336 · Cited by 41 · see citing works
Understanding the inflammation-cancer transformation in the development of primary liver cancer
Chen, H., Hu, M., Xu, F., Xu, H., She, J., & Xia, H. (2018) · Hepatoma Research · doi:10.20517/2394-5079.2018.18 · Cited by 42 · see citing works
Self-assembled fluorodendrimers in the co-delivery of fluorinated drugs and therapeutic genes
Wang, H., Hu, J., Cai, X., Xiao, J., & Cheng, Y. (2016) · Polymer Chemistry · doi:10.1039/c6py00153j · Cited by 40 · see citing works
Zheng, M., Xu, H., Liao, X., Chen, C. P., Zhang, A. L., Lu, W., Wang, L., Yang, D., Wang, J., Liu, H., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15967 · Cited by 40 · see citing works
MYC determines lineage commitment in KRAS-driven primary liver cancer development
D’Artista, L., Moschopoulou, A. A., Barozzi, I., Craig, A. J., Seehawer, M., Herrmann, L., Minnich, M., Kang, T.-W., Rist, E., Henning, M., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.02.039 · Cited by 39 · see citing works
Self-citationAwan, F. M., Naz, A., Obaid, A., Ikram, A., Ali, A., Ahmad, J., Naveed, A. K., & Janjua, H. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-11943-1 · Cited by 39 · see citing works
Xia, H., Chen, J., Gao, H., Kong, S. N., Deivasigamani, A., Shi, M., Xie, T., & Hui, K. M. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04638-4 · Cited by 39 · see citing works
Chen, W., Xiao, W., Zhang, K., Yin, X., Lai, J., Liang, L., & Dong, C. (2016) · Scientific Reports · doi:10.1038/srep22976 · Cited by 38 · see citing works
Li, S., Xu, L., Wu, G., Huang, Z., Huang, L., Zhang, F., Wei, C., Shen, Q., Li, R., Zhang, L., et al. (2023) · Advanced Science · doi:10.1002/advs.202207118 · Cited by 37 · see citing works
Carlessi, R., Köhn‐Gaone, J., Olynyk, J. K., & Tirnitz‐Parker, J. E. E. (2019) · Codon Publications eBooks · doi:10.15586/hepatocellularcarcinoma.2019 · Cited by 37 · see citing works
Li, C., Chen, J., Li, Y., Wu, B., Ye, Z., Tian, X., Wei, Y., Hao, Z., Pan, Y., Zhou, H., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.753196 · Cited by 37 · see citing works
Rashid, M. B. M. A., Toh, T. B., Silva, A., Abdullah, L. N., Ho, C., Ho, D., & Chow, E. K. (2015) · SLAS TECHNOLOGY · doi:10.1177/2211068215579612 · Cited by 36 · see citing works
Romanov, V. S., & Rudolph, K. L. (2016) · Nature Cell Biology · doi:10.1038/ncb3382 · Cited by 36 · see citing works
- Authors
- Rudalska, R., Dauch, D., Longerich, T., McJunkin, K., Wuestefeld, T., Kang, T.-W., Hohmeyer, A., Pesic, M., Leibold, J., von Thun, A., Schirmacher, P., Zuber, J., Weiss, K.-H., Powers, S., Malek, N. P., Eilers, M., Sipos, B., Lowe, S. W., Geffers, R., Laufer, S., & Zender, L.
- Affiliations
- University of Tübingen (DE)
- University Hospital Heidelberg (DE)
- Cold Spring Harbor Laboratory (US)
- German Cancer Research Center (DE)
- Research Institute of Molecular Pathology (AT)
- University of Würzburg (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Helmholtz Centre for Infection Research (DE)
- Corresponding author
- Zender, Lars
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-09-14
- Volume
- 20
- Issue
- 10
- Pages
- 1138-1146
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4587571
- OpenAlex
- W2019218097
- Cited by
- 282
- References
- 39
- Citations by year
- 2026: 2 · 2025: 18 · 2024: 12 · 2023: 14 · 2022: 26 · 2021: 35 · 2020: 17 · 2019: 31 · 2018: 27 · 2017: 30 · 2016: 30 · 2015: 37 · 2014: 3
- FWCI
- 18.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- National Cancer Institute (U01CA168409, P01CA013106, P30CA008748)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- sorafenib resistance, hepatocellular carcinoma, MAPK14, p38 MAPK, shRNA library, in vivo gene silencing, MEK/ERK signaling, multikinase inhibitor, combination therapy, drug resistance
- MeSH terms
- Sorafenib, Animals, Antineoplastic Agents, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL, Niacinamide, Phenylurea Compounds, Signal Transduction, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, RNA Interference, RNA, Small Interfering, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 14, Mice, Activating Transcription Factor 2
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