Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer
<p>Schema describing the potential interaction between MAPK inhibitors and cancer immunotherapy. In the proposed model, we suggest that MAPK inhibition may function through two distinct mechanisms. While blockade of various MAPKs limits the proliferation of tumor cells and promotes apoptosis, they may also precipitate T-cell exhaustion and/or anergy, which may potentially be reversed through the use of selective immunotherapies.</p> "> Figure 2
<p>Schema describing the potential induction of T-cell coinhibitory molecules as an unintended consequence of MAPK inhibition. In the proposed model, we suggest that MAPK inhibition may lead to the unintended upregulation of coinhibitory, immune checkpoint molecules on the surface of cancer and T cells alike, which may facilitate tumor escape from immune surveillance. mAb, monoclonal antibody.</p> ">
Abstract
:1. Introduction
2. MEK/ERK Inhibition
3. JNK Inhibition
4. p38 MAPK Inhibition
5. Other MAPK Family Members
6. Future Perspective
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Schaeffer, H.J.; Weber, M.J. Mitogen-activated protein kinases: Specific messages from ubiquitous messengers. Mol. Cell. Biol. 1999, 19, 2435–2444. [Google Scholar] [CrossRef] [Green Version]
- Zhang, W.; Liu, H.T. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002, 12, 9–18. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.; Jacobson, K.; Schaller, M.D. MAP kinases and cell migration. J. Cell Sci. 2004, 117, 4619–4628. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sohn, S.J.; Sarvis, B.K.; Cado, D.; Winoto, A. ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J. Biol. Chem. 2002, 277, 43344–43351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krueger, J.S.; Keshamouni, V.G.; Atanaskova, N.; Reddy, K.B. Temporal and quantitative regulation of mitogen-activated protein kinase (MAPK) modulates cell motility and invasion. Oncogene 2001, 20, 4209–4218. [Google Scholar] [CrossRef] [Green Version]
- Hickson, J.A.; Huo, D.Z.; Vander Griend, D.J.; Lin, A.N.; Rinker-Schaeffer, C.W.; Yamada, S.D. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 2006, 66, 2264–2270. [Google Scholar] [CrossRef] [Green Version]
- Wada, T.; Penninger, J.M. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 2004, 23, 2838–2849. [Google Scholar] [CrossRef] [Green Version]
- Wee, P.; Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017, 9, 52. [Google Scholar] [CrossRef] [Green Version]
- Amaral, T.; Sinnberg, T.; Meier, F.; Krepler, C.; Levesque, M.; Niessner, H.; Garbe, C. The mitogen-activated protein kinase pathway in melanoma part I—Activation and primary resistance mechanisms to BRAF inhibition. Eur. J. Cancer 2017, 73, 85–92. [Google Scholar] [CrossRef]
- Ellerhorst, J.A.; Ekmekcioglu, S.; Johnson, M.K.; Cooke, C.P.; Johnson, M.M.; Grimm, E.A. Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma. Oncogene 2006, 25, 3956–3962. [Google Scholar] [CrossRef] [Green Version]
- Nan, X.; Tamguney, T.M.; Collisson, E.A.; Lin, L.J.; Pitt, C.; Galeas, J.; Lewis, S.; Gray, J.W.; McCormick, F.; Chu, S. Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway. Proc. Natl. Acad. Sci. USA 2015, 112, 7996–8001. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schonwasser, D.C.; Marais, R.M.; Marshall, C.J.; Parker, P.J. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. Cell. Biol. 1998, 18, 790–798. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Plotnikov, A.; Zehorai, E.; Procaccia, S.; Seger, R. The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta 2011, 1813, 1619–1633. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cicenas, J.; Zalyte, E.; Rimkus, A.; Dapkus, D.; Noreika, R.; Urbonavicius, S. JNK, p38, ERK, and SGK1 inhibitors in cancer. Cancers 2017, 10, 1. [Google Scholar] [CrossRef] [Green Version]
- Lapinski, P.E.; King, P.D. Regulation of Ras signal transduction during T cell development and activation. Am. J. Clin. Exp. Immunol. 2012, 1, 147–153. [Google Scholar]
- Schafer, P.H.; Wang, L.; Wadsworth, S.A.; Davis, J.E.; Siekierka, J.J. T cell activation signals up-regulate p38 mitogen-activated protein kinase activity and induce TNF-alpha production in a manner distinct from LPS activation of monocytes. J. Immunol. 1999, 162, 659–668. [Google Scholar]
- D’Souza, W.N.; Chang, C.F.; Fischer, A.M.; Li, M.; Hedrick, S.M. The Erk2 MAPK regulates CD8 T cell proliferation and survival. J. Immunol. 2008, 181, 7617–7629. [Google Scholar] [CrossRef]
- Atsaves, V.; Leventaki, V.; Rassidakis, G.Z.; Claret, F.X. AP-1 transcription factors as regulators of immune responses in cancer. Cancers 2019, 11, 1037. [Google Scholar] [CrossRef] [Green Version]
- Dushyanthen, S.; Teo, Z.L.; Caramia, F.; Savas, P.; Mintoff, C.P.; Virassamy, B.; Henderson, M.A.; Luen, S.J.; Mansour, M.; Kershaw, M.H.; et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat. Commun. 2017, 8, 606. [Google Scholar] [CrossRef]
- Boulton, T.G.; Nye, S.H.; Robbins, D.J.; Ip, N.Y.; Radziejewska, E.; Morgenbesser, S.D.; Depinho, R.A.; Panayotatos, N.; Cobb, M.H.; Yancopoulos, G.D. Erks—A family of protein-serine threonine kinases that are activated and tyrosine phosphorylated in response to insulin and Ngf. Cell 1991, 65, 663–675. [Google Scholar] [CrossRef]
- Li, L.; Zhao, G.D.; Shi, Z.; Qi, L.L.; Zhou, L.Y.; Fu, Z.X. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol. Lett. 2016, 12, 3045–3050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yujiri, T.; Sather, S.; Fanger, G.R.; Johnson, G.L. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science 1998, 282, 1911–1914. [Google Scholar] [CrossRef] [PubMed]
- Fischer, A.M.; Katayama, C.D.; Pages, G.; Pouyssegur, J.; Hedrick, S.M. The role of erk1 and erk2 in multiple stages of T cell development. Immunity 2005, 23, 431–443. [Google Scholar] [CrossRef] [PubMed]
- Lafont, V.; Ottones, F.; Liautard, J.; Favero, J. Evidence for a p21 (ras)/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes. J. Biol. Chem. 1999, 274, 25743–25748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nekrasova, T.; Shive, C.; Gao, Y.H.; Kawamura, K.; Guardia, R.; Landreth, G.; Forsthuber, T.G. ERK1-deficient mice show normal T cell effector function and are highly susceptible to experimental autoimmune encephalomyelitis. J. Immunol. 2005, 175, 2374–2380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dillon, T.J.; Carey, K.D.; Wetzel, S.A.; Parker, D.C.; Stork, P.J. Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4. Mol. Cell. Biol. 2005, 25, 4117–4128. [Google Scholar] [CrossRef] [Green Version]
- Ohnishi, H.; Takeda, K.; Domenico, J.; Lucas, J.J.; Miyahara, N.; Swasey, C.H.; Dakhama, A.; Gelfand, E.W. Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8(+) T cell-mediated airway hyperresponsiveness and inflammation. J. Allergy Clin. Immun. 2009, 123, 249–257. [Google Scholar] [CrossRef]
- Ohori, M.; Kinoshita, T.; Okubo, M.; Sato, K.; Yamazaki, A.; Arakawa, H.; Nishimura, S.; Inamura, N.; Nakajima, H.; Neya, M.; et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem. Biophys. Res. Commun. 2005, 336, 357–363. [Google Scholar] [CrossRef]
- Sullivan, R.J.; Infante, J.R.; Janku, F.; Wong, D.J.L.; Sosman, J.A.; Keedy, V.; Patel, M.R.; Shapiro, G.I.; Mier, J.W.; Tolcher, A.W.; et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: Results of a phase I dose-escalation and expansion study. Cancer Discov. 2018, 8, 184–195. [Google Scholar] [CrossRef] [Green Version]
- Aaron, C.P.; Tandri, H.; Barr, R.G.; Johnson, W.C.; Bagiella, E.; Chahal, H.; Jain, A.; Kizer, J.R.; Bertoni, A.G.; Lima, J.A.; et al. Physical activity and right ventricular structure and function: The MESA-right ventricle study. Am. J. Respir. Crit. Care Med. 2011, 183, 396–404. [Google Scholar] [CrossRef]
- Kirouac, D.; Schaefer, G.; Chan, J.; Merchant, M.; Orr, C.; Liu, L.; Huang, A.; Moffat, J.; Gadkar, K.; Ramanujan, S. Clinical responses to ERK inhibitor (GDC-0994) treatment combinations predicted using a Quantitative Systems Pharmacology model of MAPK signaling in BRAF(V600E)-mutant colorectal cancer. Eur. J. Cancer 2016, 69, S20. [Google Scholar] [CrossRef]
- Moschos, S.J.; Sullivan, R.J.; Hwu, W.J.; Ramanathan, R.K.; Adjei, A.A.; Fong, P.C.; Shapira-Frommer, R.; Tawbi, H.A.; Rubino, J.; Rush, T.S.; et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight 2018, 3. [Google Scholar] [CrossRef] [PubMed]
- Bavaria, M.N.; Jin, S.; Ray, R.M.; Johnson, L.R. The mechanism by which MEK/ERK regulates JNK and p38 activity in polyamine depleted IEC-6 cells during apoptosis. Apoptosis 2014, 19, 467–479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ritt, D.A.; Abreu-Blanco, M.T.; Bindu, L.; Durrant, D.E.; Zhou, M.; Specht, S.I.; Stephen, A.G.; Holderfield, M.; Morrison, D.K. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit. Mol. Cell 2016, 64, 875–887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abe, H.; Kikuchi, S.; Hayakawa, K.; Iida, T.; Nagahashi, N.; Maeda, K.; Sakamoto, J.; Matsumoto, N.; Miura, T.; Matsumura, K.; et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO solvate). ACS Med. Chem. Lett. 2011, 2, 320–324. [Google Scholar] [CrossRef]
- Shapiro, G.I.; LoRusso, P.; Kwak, E.; Pandya, S.; Rudin, C.M.; Kurkjian, C.; Cleary, J.M.; Pilat, M.J.; Jones, S.; de Crespigny, A.; et al. Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors. Investig. New Drugs 2019. [Google Scholar] [CrossRef]
- Bardia, A.; Gounder, M.; Rodon, J.; Janku, F.; Lolkema, M.P.; Stephenson, J.J.; Bedard, P.L.; Schuler, M.; Sessa, C.; LoRusso, P.; et al. Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with advanced solid tumors with RAS/RAF Alterations. Oncologist 2019. [Google Scholar] [CrossRef] [Green Version]
- Banerjee, A.; Jakacki, R.I.; Onar-Thomas, A.; Wu, S.; Nicolaides, T.; Young Poussaint, T.; Fangusaro, J.; Phillips, J.; Perry, A.; Turner, D.; et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: A Pediatric Brain Tumor Consortium (PBTC) study. Neuro-Oncology 2017, 19, 1135–1144. [Google Scholar] [CrossRef] [Green Version]
- Stutvoet, T.S.; Kol, A.; de Vries, E.G.E.; de Bruyn, M.; Fehrmann, R.S.N.; van Scheltinga, A.G.T.T.; de Jong, S. MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells. J. Pathol. 2019, 249, 52–64. [Google Scholar] [CrossRef] [Green Version]
- Ebert, P.J.R.; Cheung, J.; Yang, Y.; McNamara, E.; Hong, R.; Moskalenko, M.; Gould, S.E.; Maecker, H.; Irving, B.A.; Kim, J.M.; et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 2016, 44, 609–621. [Google Scholar] [CrossRef] [Green Version]
- Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 2000, 103, 239–252. [Google Scholar] [CrossRef] [Green Version]
- Cargnello, M.; Roux, P.P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 2011, 75, 50–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- O’Hayre, M.; Degese, M.S.; Gutkind, J.S. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr. Opin. Cell Biol. 2014, 27, 126–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seki, E.; Brenner, D.A.; Karin, M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 2012, 143, 307–320. [Google Scholar] [CrossRef] [Green Version]
- Dong, C.; Yang, D.D.; Tournier, C.; Whitmarsh, A.J.; Xu, J.; Davis, R.J.; Flavell, R.A. JNK is required for effector T-cell function but not for T-cell activation. Nature 2000, 405, 91–94. [Google Scholar] [CrossRef]
- Behrens, A.; Sabapathy, K.; Graef, I.; Cleary, M.; Crabtree, G.R.; Wagner, E.F. Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT). Proc. Natl. Acad. Sci. USA 2001, 98, 1769–1774. [Google Scholar] [CrossRef] [Green Version]
- Su, B.; Cheng, J.K.; Yang, J.H.; Guo, Z.J. MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J. Biol. Chem. 2001, 276, 14784–14790. [Google Scholar] [CrossRef] [Green Version]
- Conze, D.; Krahl, T.; Kennedy, N.; Weiss, L.; Lumsden, J.; Hess, P.; Flavell, R.A.; Le Gros, G.; Davis, R.J.; Rincon, M. C-jun NH2-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J. Exp. Med. 2002, 195, 811–823. [Google Scholar] [CrossRef] [Green Version]
- Bennett, B.L.; Sasaki, D.T.; Murray, B.W.; O’Leary, E.C.; Sakata, S.T.; Xu, W.; Leisten, J.C.; Motiwala, A.; Pierce, S.; Satoh, Y.; et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 2001, 98, 13681–13686. [Google Scholar] [CrossRef] [Green Version]
- Zhang, T.; Inesta-Vaquera, F.; Niepel, M.; Zhang, J.; Ficarro, S.B.; Machleidt, T.; Xie, T.; Marto, J.A.; Kim, N.; Sim, T.; et al. Discovery of potent and selective covalent inhibitors of JNK. Chem. Biol. 2012, 19, 140–154. [Google Scholar] [CrossRef] [Green Version]
- Ma, F.Y.; Flanc, R.S.; Tesch, G.H.; Han, Y.; Atkins, R.C.; Bennett, B.L.; Friedman, G.C.; Fan, J.H.; Nikolic-Paterson, D.J. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J. Am. Soc. Nephrol. 2007, 18, 472–484. [Google Scholar] [CrossRef] [PubMed]
- Okada, M.; Kuramoto, K.; Takeda, H.; Watarai, H.; Sakaki, H.; Seino, S.; Seino, M.; Suzuki, S.; Kitanaka, C. The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. Oncotarget 2016, 7, 27021–27032. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, Y.; Spigolon, G.; Bonny, C.; Culman, J.; Vercelli, A.; Herdegen, T. The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria. Mol. Cell. Neurosci. 2012, 49, 300–310. [Google Scholar] [CrossRef] [PubMed]
- Stebbins, J.L.; De, S.K.; Machleidt, T.; Becattini, B.; Vazquez, J.; Kuntzen, C.; Chen, L.H.; Cellitti, J.F.; Riel-Mehan, M.; Emdadi, A.; et al. Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proc. Natl. Acad. Sci. USA 2008, 105, 16809–16813. [Google Scholar] [CrossRef] [Green Version]
- Bubici, C.; Papa, S. JNK signalling in cancer: In need of new, smarter therapeutic targets. Br. J. Pharmacol. 2014, 171, 24–37. [Google Scholar] [CrossRef]
- Mehrotra, S.; Chhabra, A.; Chattopadhyay, S.; Dorsky, D.I.; Chakraborty, N.G.; Mukherji, B. Rescuing melanoma epitope-specific cytolytic T lymphocytes from activation-induced cell death, by SP600125, an inhibitor of JNK: Implications in cancer immunotherapy. J. Immunol. 2004, 173, 6017–6024. [Google Scholar] [CrossRef] [Green Version]
- Hu, M.C.; Wang, Y.P.; Mikhail, A.; Qiu, W.R.; Tan, T.H. Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines. J. Biol. Chem. 1999, 274, 7095–7102. [Google Scholar] [CrossRef] [Green Version]
- Cuenda, A.; Rousseau, S. P38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta 2007, 1773, 1358–1375. [Google Scholar] [CrossRef] [Green Version]
- Donnelly, S.M.; Paplomata, E.; Peake, B.M.; Sanabria, E.; Chen, Z.; Nahta, R. P38 MAPK contributes to resistance and invasiveness of HER2—Overexpressing breast cancer. Curr. Med. Chem. 2014, 21, 501–510. [Google Scholar] [CrossRef] [Green Version]
- Farhat, F.; Daulay, E.R.; Chrestella, J.; Asnir, R.A.; Yudhistira, A.; Susilo, R.R. Correlation of P38 mitogen-activated protein kinase expression to clinical stage in nasopharyngeal carcinoma. Open Access Maced. J. Med. Sci. 2018, 6, 1982–1985. [Google Scholar] [CrossRef] [Green Version]
- Guo, X.L.; Ma, N.N.; Wang, J.; Song, J.R.; Bu, X.X.; Cheng, Y.; Sun, K.; Xiong, H.Y.; Jiang, G.C.; Zhang, B.H.; et al. Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 2008, 8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhong, Y.; Naito, Y.; Cope, L.; Naranjo-Suarez, S.; Saunders, T.; Hong, S.M.; Goggins, M.G.; Herman, J.M.; Wolfgang, C.L.; Iacobuzio-Donahue, C.A. Functional p38 MAPK identified by biomarker profiling of pancreatic cancer restrains growth through JNK inhibition and correlates with improved survival. Clin. Cancer Res. 2014, 20, 6200–6211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dodeller, F.; Schulze-Koops, H. The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells. Arthritis Res. Ther. 2006, 8, 205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Noubade, R.; Krementsov, D.N.; Del Rio, R.; Thornton, T.; Nagaleekar, V.; Saligrama, N.; Spitzack, A.; Spach, K.; Sabio, G.; Davis, R.J.; et al. Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis. Blood 2011, 118, 3290–3300. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.C.; Hsu, S.C.; Shih, H.M.; Lai, M.Z. Nuclear factor of activated T cells c is a target of p38 mitogen-activated protein kinase in T cells. Mol. Cell. Biol. 2003, 23, 6442–6454. [Google Scholar] [CrossRef] [Green Version]
- Klein-Hessling, S.; Muhammad, K.; Klein, M.; Pusch, T.; Rudolf, R.; Floter, J.; Qureischi, M.; Beilhack, A.; Vaeth, M.; Kummerow, C.; et al. NFATc1 controls the cytotoxicity of CD8+ T cells. Nat. Commun. 2017, 8, 511. [Google Scholar] [CrossRef] [Green Version]
- Ohkusu-Tsukada, K.; Toda, M.; Udono, H.; Kawakami, Y.; Takahashi, K. Targeted inhibition of IL-10-secreting CD25- Treg via p38 MAPK suppression in cancer immunotherapy. Eur. J. Immunol. 2010, 40, 1011–1021. [Google Scholar] [CrossRef]
- Laufer, S.; Lehmann, F. Investigations of SCIO-469-like compounds for the inhibition of p38 MAP kinase. Bioorg. Med. Chem. Lett. 2009, 19, 1461–1464. [Google Scholar] [CrossRef]
- Kuma, Y.; Sabio, G.; Bain, J.; Shpiro, N.; Marquez, R.; Cuenda, A. BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo. J. Biol. Chem. 2005, 280, 19472–19479. [Google Scholar] [CrossRef] [Green Version]
- Campbell, R.M.; Anderson, B.D.; Brooks, N.A.; Brooks, H.B.; Chan, E.M.; De Dios, A.; Gilmour, R.; Graff, J.R.; Jambrina, E.; Mader, M.; et al. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol. Cancer Ther. 2014, 13, 364–374. [Google Scholar] [CrossRef] [Green Version]
- Duffy, J.P.; Harrington, E.M.; Salituro, F.G.; Cochran, J.E.; Green, J.; Gao, H.A.; Bemis, G.W.; Evindar, G.; Galullo, V.P.; Ford, P.J.; et al. The discovery of VX-745: A Novel and selective p38 alpha kinase inhibitor. ACS Med. Chem. Lett. 2011, 2, 758–763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barancik, M.; Bohacova, V.; Kvackajova, J.; Hudecova, S.; Krizanova, O.; Breier, A. SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur. J. Pharm. Sci. 2001, 14, 29–36. [Google Scholar] [CrossRef]
- Selness, S.R.; Devraj, R.V.; Devadas, B.; Walker, J.K.; Boehm, T.L.; Durley, R.C.; Shieh, H.; Xing, L.; Rucker, P.V.; Jerome, K.D.; et al. Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase. Bioorg. Med. Chem. Lett. 2011, 21, 4066–4071. [Google Scholar] [CrossRef] [PubMed]
- Jin, X.; Mo, Q.; Zhang, Y.; Gao, Y.; Wu, Y.; Li, J.; Hao, X.; Ma, D.; Gao, Q.; Chen, P. The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer. Cancer Biol. Ther. 2016, 17, 566–576. [Google Scholar] [CrossRef]
- Malm, S.W.; Hanke, N.T.; Gill, A.; Carbajal, L.; Baker, A.F. The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines. J. Exp. Clin. Cancer Res. 2015, 34, 31. [Google Scholar] [CrossRef] [Green Version]
- Kuhnol, C.; Herbarth, M.; Foll, J.; Staege, M.S.; Kramm, C. CD137 stimulation and p38 MAPK inhibition improve reactivity in an in vitro model of glioblastoma immunotherapy. Cancer Immunol. Immunother. 2013, 62, 1797–1809. [Google Scholar] [CrossRef]
- Lu, Y.; Zhang, M.; Wang, S.; Hong, B.; Wang, Z.; Li, H.; Zheng, Y.; Yang, J.; Davis, R.E.; Qian, J.; et al. P38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. Nat. Commun. 2014, 5, 4229. [Google Scholar] [CrossRef] [Green Version]
- Hu, M.C.; Wang, Y.; Qiu, W.R.; Mikhail, A.; Meyer, C.F.; Tan, T.H. Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IkappaB kinases (IKK-alpha/beta) and IKK-beta is a developmentally regulated protein kinase. Oncogene 1999, 18, 5514–5524. [Google Scholar] [CrossRef] [Green Version]
- Alzabin, S.; Bhardwaj, N.; Kiefer, F.; Sawasdikosol, S.; Burakoff, S. Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J. Immunol. 2009, 182, 6187–6194. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.; Song, X.; Logsdon, C.; Zhou, G.; Evans, D.B.; Abbruzzese, J.L.; Hamilton, S.R.; Tan, T.H.; Wang, H. Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer. Cancer Res. 2009, 69, 1063–1070. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.J.; Song, L.J.; Yang, S.; Zhang, W.J.; Lu, P.W.; Li, S.L.; Li, H.X.; Wang, L.X. HPK1 positive expression associated with longer overall survival in patients with estrogen receptor-positive invasive ductal carcinoma-not otherwise specified. Mol. Med. Rep. 2017, 16, 4634–4642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shui, J.W.; Boomer, J.S.; Han, J.; Xu, J.; Dement, G.A.; Zhou, G.; Tan, T.H. Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. Nat. Immunol. 2007, 8, 84–91. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Curtin, J.; You, D.; Hillerman, S.; Li-Wang, B.; Eraslan, R.; Xie, J.; Swanson, J.; Ho, C.P.; Oppenheimer, S.; et al. Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance. PLoS ONE 2019, 14, e0212670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Diener, K.; Wang, X.S.; Chen, C.; Meyer, C.F.; Keesler, G.; Zukowski, M.; Tan, T.H.; Yao, Z. Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc. Natl. Acad. Sci. USA 1997, 94, 9687–9692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chuang, H.C.; Tan, T.H. MAP4K3/GLK in autoimmune disease, cancer and aging. J. Biomed. Sci. 2019, 26, 82. [Google Scholar] [CrossRef]
- Hsu, C.P.; Chuang, H.C.; Lee, M.C.; Tsou, H.H.; Lee, L.W.; Li, J.P.; Tan, T.H. GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer. Oncotarget 2016, 7, 41748–41757. [Google Scholar] [CrossRef] [Green Version]
- Chuang, H.C.; Tsai, C.Y.; Hsueh, C.H.; Tan, T.H. GLK-IKKbeta signaling induces dimerization and translocation of the AhR-RORgammat complex in IL-17A induction and autoimmune disease. Sci. Adv. 2018, 4, eaat5401. [Google Scholar] [CrossRef] [Green Version]
- Chuang, H.C.; Chen, Y.M.; Chen, M.H.; Hung, W.T.; Yang, H.Y.; Tseng, Y.H.; Tan, T.H. AhR-ROR-gamma t complex is a therapeutic target for MAP4K3/GLK(high)IL-17A(high) subpopulation of systemic lupus erythematosus. FASEB J. 2019, 33, 11469–11480. [Google Scholar] [CrossRef] [Green Version]
- Xu, W.W.; Dong, J.; Zheng, Y.W.; Zhou, J.; Yuan, Y.; Ta, H.M.; Miller, H.E.; Olson, M.; Rajasekaran, K.; Ernstoff, M.S.; et al. Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression. Cancer Immunol. Res. 2019, 7, 1497–1510. [Google Scholar] [CrossRef]
- Seimetz, D.; Heller, K.; Richter, J. Approval of first CAR-Ts: Have we solved all hurdles for ATMPs? Cell Med. 2019, 11. [Google Scholar] [CrossRef] [Green Version]
MEK/ERK Member | Inhibitor | Combination with Immunotherapy | Cancer Type |
---|---|---|---|
MEK1/2 | Trametinib | 4-1BB and OX40 agonist antibodies | Breast cancer [19] |
Selumetinib | Anti-EGFR antibody | Lung adenocarcinoma [39] | |
G-38963 | Anti-PD-L1 antibody | Colon carcinoma [40] | |
ERK1/2 | BVD523 | Positive outcomes in patients previously treated with immunotherapy | NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors [29] |
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Kumar, S.; Principe, D.R.; Singh, S.K.; Viswakarma, N.; Sondarva, G.; Rana, B.; Rana, A. Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer. Pharmaceuticals 2020, 13, 9. https://doi.org/10.3390/ph13010009
Kumar S, Principe DR, Singh SK, Viswakarma N, Sondarva G, Rana B, Rana A. Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer. Pharmaceuticals. 2020; 13(1):9. https://doi.org/10.3390/ph13010009
Chicago/Turabian StyleKumar, Sandeep, Daniel R. Principe, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Basabi Rana, and Ajay Rana. 2020. "Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer" Pharmaceuticals 13, no. 1: 9. https://doi.org/10.3390/ph13010009