Pharmaceutical SH2 domain–containing protein tyrosine phosphatase 2 inhibition suppresses primary and metastasized liver tumors by provoking hepatic innate immunity
Open accessAbstract
Background and Aims: SH2 domain–containing protein tyrosine phosphatase 2 (Shp2) is the first identified pro‐oncogenic tyrosine phosphatase that acts downstream of receptor tyrosine kinases (RTKs) to promote Ras–extracellular signal–regulated kinase signaling. However, this phosphatase was also shown to be antitumorigenic in HCC. This study is aimed at deciphering paradoxical Shp2 functions and mechanisms in hepatocarcinogenesis and at exploring its value as a pharmaceutical target in HCC therapy. Approaches and Results: We took both genetic and pharmaceutical approaches to examine the effects of Shp2 inhibition on primary liver cancers driven by various oncogenes and on metastasized liver tumors. We show here that the catalytic activity of Shp2 was essential for relay of oncogenic signals from RTKs in HCC and that chemical inhibition of Shp2 robustly suppressed HCC driven by RTKs. However, in contrast to a tumor‐promoting hepatic niche generated by genetically deleting Shp2 in hepatocytes, treatment with a specific Shp2 inhibitor had a tumor‐suppressing effect on metastasized liver tumor progression. Mechanistically, the Shp2 inhibitor enhanced antitumor innate immunity by down‐regulating inflammatory cytokines, suppressing the chemokine (C‐C motif) receptor 5 signaling axis, but up‐regulating interferon‐β secretion. Conclusions: These results unveil complex mechanisms for the tumor‐suppressing effect of pharmaceutical Shp2 inhibition in the liver immune environment. We provide a proof of principle for clinical trials with specific Shp2 inhibitors in patients with primary and metastasized liver cancer.
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While our findings suggest that SHP2i and SOS1i may induce the same efficacy, inhibiting SOS1 avoids some of the pleiotropic effects of SHP2 inhibitors, potentially resulting in better clinical tolerability.
“Of note, while our findings suggest that SHP2i and SOS1i may induce the same efficacy, inhibiting SOS1 avoids some of the pleiotropic effects of SHP2 inhibitors56,57, potentially resulting in better clinical tolerability.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [57]
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Cites
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21492 · Cited by 84,109 · see citing works
T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., et al. (2017) · Science · doi:10.1126/science.aaf1292 · Cited by 1,689 · see citing works
Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma
Llovet, J. M., De Baere, T., Kulik, L., Haber, P. K., Greten, T. F., Meyer, T., & Lencioni, R. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00395-0 · Cited by 1,044 · see citing works
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
Chen, Y.-N. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcia-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H.-T., Chen, Z., Cooke, V. G., et al. (2016) · Nature · doi:10.1038/nature18621 · Cited by 925 · see citing works
SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2
Rui, L., Yuan, M., Frantz, D., Shoelson, S., & White, M. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200444200 · Cited by 904 · see citing works
M2b macrophage polarization and its roles in diseases
Wang, L., Zhang, S.-X., Wu, H., Rong, X., & Guo, J. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ru1018-378rr · Cited by 891 · see citing works
Halama, N., Zoernig, I., Berthel, A., Kahlert, C., Klupp, F., Suarez‐Carmona, M., Sütterlin, T., Brand, K., Krauss, J., Lasitschka, F., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.03.005 · Cited by 497 · see citing works
Nicholson, S. E., De Souza, D., Fabri, L. J., Corbin, J., Willson, T. A., Zhang, J.-G., Silva, A., Asimakis, M., Farley, A., Nash, A. D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.100135197 · Cited by 456 · see citing works
CCR1 and CCR5 promote hepatic fibrosis in mice
Seki, E., De Minicis, S., Gwak, G.-Y., Kluwe, J., Inokuchi, S., Bursill, C. A., Llovet, J. M., Brenner, D. A., & Schwabe, R. F. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37444 · Cited by 431 · see citing works
Hydrodynamic Transfection for Generation of Novel Mouse Models for Liver Cancer Research
Chen, X., & Calvisi, D. F. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.12.002 · Cited by 430 · see citing works
Kaposi-Novák, P. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27236 · Cited by 397 · see citing works
Schmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12848 · Cited by 388 · see citing works
PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase
Chan, R. J., & Feng, G. (2006) · Blood · doi:10.1182/blood-2006-07-028829 · Cited by 378 · see citing works
Self-citationPtpn11/Shp2 Acts as a Tumor Suppressor in Hepatocellular Carcinogenesis
Bard-Chapeau, E. A., Li, S., Ding, J., Zhang, S. S., Zhu, H. H., Princen, F., Fang, D. D., Han, T., Bailly-Maitre, B., Poli, V., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.023 · Cited by 332 · see citing works
Self-citationSHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
Mainardi, S., Mulero-Sánchez, A., Prahallad, A., Germano, G., Bosma, A., Krimpenfort, P., Lieftink, C., Steinberg, J. D., de Wit, N., Gonçalves-Ribeiro, S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0023-9 · Cited by 320 · cited 1× · see citing works
“[15] This and similar compounds have been shown to effectively suppress tumor growth in various types of cancer, including lung cancer,[16] gastrointestinal cancer,[17] breast cancer,[18] and neuroblastoma[19]; and clinical trials are ongoing.”
BackgroundKitade, H., Sawamoto, K., Nagashimada, M., Inoue, H., Yamamoto, Y., Sai, Y., Takamura, T., Yamamoto, H., Miyamoto, K., Ginsberg, H. N., et al. (2012) · Diabetes · doi:10.2337/db11-1506 · Cited by 292 · see citing works
Wang, R., Ferrell, L. D., Faouzi, S., Maher, J. J., & Bishop, J. M. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.5.1023 · Cited by 281 · see citing works
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0022-x · Cited by 266 · see citing works
Self-citationLi, M., Sun, X., Zhao, J., Xia, L., Li, J., Xu, M., Wang, B., Guo, H., Yu, C., Gao, Y., et al. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0279-0 · Cited by 225 · see citing works
Ahmed, T. A., Adamopoulos, C., Karoulia, Z., Wu, X., Sachidanandam, R., Aaronson, S. A., & Poulikakos, P. I. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.013 · Cited by 214 · see citing works
Wang, B., Zhang, W., Jankovic, V., Golubov, J., Poon, P., Oswald, E. M., Gurer, C., Wei, J., Ramos, I., Wu, Q., et al. (2018) · Science Immunology · doi:10.1126/sciimmunol.aat7061 · Cited by 167 · see citing works
IRF5 controls both acute and chronic inflammation
Weiss, M., Byrne, A. J., Blazek, K. D., Saliba, D. G., Pease, J. E., Perocheau, D. P. B., Feldmann, M., & Udalova, I. A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1506254112 · Cited by 164 · see citing works
Daveau, M., Scotté, M., François, A., et al. (2003) · Molecular Carcinogenesis · doi:10.1002/mc.10103 · Cited by 127 · see citing works
Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection
Bard-Chapeau, E. A., Yuan, J., Droin, N. M., Long, S., Zhang, E. E., Nguyen, T. V., & Feng, G. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02253-05 · Cited by 115 · see citing works
Self-citationXiao, P., Zhang, H., Zhang, Y., Zheng, M., Liu, R., Zhao, Y., Zhang, X., Cheng, H., Cao, Q., & Ke, Y. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181198 · Cited by 97 · see citing works
Alterations and hypermethylation of thep14ARF gene in gastric cancer
Iida, S., Akiyama, Y., Nakajima, T., Ichikawa, W., Nihei, Z., Sugihara, K., & Yuasa, Y. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20000901)87:5 · Cited by 88 · see citing works
Inflammation-Induced Hepatocellular Carcinoma Is Dependent on Ccr5 in Mice
Barashi, N., Weiss, I. D., Wald, O., Wald, H., Beider, K., Abraham, M., Klein, S., Goldenberg, D., Axelrod, J. H., Pikarsky, E., et al. (2013) · Hepatology · doi:10.1002/hep.26403 · Cited by 77 · see citing works
Osada, S., Kanematsu, M., Imai, H., et al. (2008) · PubMed · Cited by 67 · see citing works
Liu, J. J., Li, Y., Chen, W. S., Liang, Y., Wang, G., Zong, M., Kaneko, K., Xu, R., Karin, M., & Feng, G. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.02.014 · Cited by 64 · see citing works
Self-citationValencia-Sama, I., Ladumor, Y., Kee, L., Adderley, T., Christopher, G., Robinson, C. M., Kano, Y., Ohh, M., & Irwin, M. S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3822 · Cited by 62 · see citing works
Forrai, A., Boyle, K., Hart, A. H., Hartley, L., Rakar, S., Willson, T. A., Simpson, K., Roberts, A. W., Alexander, W. S., Voss, A. K., et al. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0323 · Cited by 60 · see citing works
Wen, L., Xin, B., Wu, P., Lin, C.-H., Peng, C., Wang, G.-W., Lee, J., Lu, L.-F., & Feng, G.-S. (2019) · Hepatology · doi:10.1002/hep.30528 · Cited by 58 · see citing works
Self-citationDual faces of SH2-containing protein-tyrosine phosphatase Shp2/PTPN11 in tumorigenesis
Li, S., Hsu, D. D., Wang, H., & Feng, G. (2012) · Frontiers of Medicine · doi:10.1007/s11684-012-0216-4 · Cited by 55 · see citing works
Self-citationChen, W. S., Liang, Y., Zong, M., Liu, J. J., Kaneko, K., Hanley, K. L., Zhang, K., & Feng, G.-S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109974 · Cited by 50 · see citing works
Self-citationGui, Y., Yeganeh, M., Donates, Y.-C., Tobelaim, W.-S., Chababi, W., Mayhue, M., Yoshimura, A., Ramanathan, S., Saucier, C., & Ilangumaran, S. (2015) · Oncogene · doi:10.1038/onc.2015.20 · Cited by 44 · see citing works
Luo, X.-L., Liao, R., Hanley, K. L., Zhu, H., Malo, K. N., Hernandez, C., Wei, X., Varki, N., Alderson, N. B., Chu, C., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.048 · Cited by 42 · see citing works
Self-citationBing, X., Yang, M., Wu, P., Du, L., Deng, X., Hui, E., & Feng, G. (2021) · Hepatology · doi:10.1002/hep.32266 · Cited by 28 · see citing works
Self-citationMarx‐Stoelting, P., Borowiak, M., Knorpp, T., Birchmeier, C., Buchmann, A., & Schwarz, M. (2008) · International Journal of Cancer · doi:10.1002/ijc.24167 · Cited by 27 · see citing works
Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions
Lee, J., Liao, R., Wang, G., Yang, B.-H., Luo, X., Varki, N. M., Qiu, S., Ren, B., Fu, W., & Feng, G. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.064 · Cited by 26 · see citing works
Self-citationTumor-associated macrophages (TAMs) depend on Shp2 for their anti-tumor roles in colorectal cancer.
Wang, S., Yao, Y., Li, H., et al. (2019) · PubMed · Cited by 26 · see citing works
Hanley, K. L., Liang, Y., Wang, G., Lin, X., Yang, M., Karin, M., Fu, W., & Feng, G. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0479 · Cited by 13 · see citing works
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Thatikonda, V., Lyu, H., Jurado, S., Kostyrko, K., Bristow, C. A., Albrecht, C., Alpar, D., Arnhof, H., Bergner, O., Bosch, K., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00800-6 · Cited by 76 · see citing works
- Authors
- Liu, J. J., Xin, B., Du, L., Chen, L., Long, Y., & Feng, G.
- Affiliations
- University of California San Diego (US)
- Department of Pathology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California, USA
- Corresponding author
- Feng, Gen‐Sheng
- Venue
- Hepatology
- Published
- 2023-04-17
- Volume
- 77
- Issue
- 5
- Pages
- 1512-1526
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC9948275
- OpenAlex
- W4225295109
- Cited by
- 11
- References
- 41
- Citations by year
- 2026: 2 · 2024: 7 · 2023: 1 · 2022: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine (FA1-00607)
- Israel National Institute for Health Policy Research
- National Institutes of Health
- University of California, San Diego (FA1-00607, P30 NS047101)
- National Institute on Aging (P01AG073084)
- National Cancer Institute (R01CA236074, R01CA239629, P30CA023100)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128320)
- National Institute of Neurological Disorders and Stroke (P30NS047101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- SHP2, protein tyrosine phosphatase inhibition, hepatocellular carcinoma, liver cancer metastasis, receptor tyrosine kinase, Ras/ERK signaling, hepatic innate immunity, interferon-beta, inflammatory cytokines, antitumor immunity
- MeSH terms
- Pharmaceutical Preparations, Carcinoma, Hepatocellular, Humans, Immunity, Innate, Liver Neoplasms, Tyrosine, Receptor Protein-Tyrosine Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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