MEK is a key gatekeeper in the MAPK signalling pathway
The mitogen-activated protein kinase (MAPK) signalling pathway mediates cellular processes such as gene expression, cellular growth, and survival.1,2
MEK also plays a critical role in immune signalling.3
- The RAF/MEK/ERK pathway is crucial for T-cell development, activation, and differentiation
Dysregulated Raf-MEK-ERK signalling is associated with tumour growth
MAPK signalling plays a role in different types of cancer, including melanoma, colorectal cancer, and lung cancer.1,4 While abnormal MAPK signalling is well known for its effect on tumour-cell proliferation and survival, emerging research has found this pathway can also be exploited by tumours to escape the antitumour immune response.5-8
The MAPK pathway has been shown to downregulate major histocompatibility complex (MHC) class I expression in a number of tumour types, which may serve as a mechanism of immune escape by tumour cells.9-12
Decreased expression of MHC class I is associated with reduced sensitivity to lysis by cytotoxic T cells, possibly due to poor recognition of tumour cells by cytotoxic T cells.9-12
Persistent TCR stimulation of T cells may lead to T-cell exhaustion and apoptosis mediated by MAPK signalling, and also drive expression of immune checkpoint molecules.13
MEK pathway signalling overrides cell death signalling, which may limit the release of tumour antigens.7,8
MEK inhibition may address these mechanisms of immune escape by increasing tumour immunogenicity and enhancing antitumour T-cell activity
MEK inhibition may increase tumour antigen presentation via upregulation of MHC class I expression, leading to recognition and killing of tumour cells by T cells.11,12
- In preclinical studies, MAPK inhibition or MEK inhibition were associated with increased expression of MHC class I9-13
In a preclinical study, MEK inhibition limited the exhaustive apoptosis of CD8+ T cells caused by chronic T-cell receptor stimulation, leading to intratumoural T-cell accumulation.13,14
- The recruitment of T cells may make tumours become more inflamed, thus priming them for immune checkpoint inhibition
Inhibition of MEK signalling may promote cell death by increasing release of tumour-specific antigens.7,8,15
Targeting MEK and PD-L1 may have a synergistic effect on restoring cancer immunity
Because tumours employ multiple mechanisms to evade the immune response, an approach involving a combination of immunotherapy targets to re-establish proper antitumour T-cell activity may provide therapeutic benefit.15,16
Roche is actively investigating MEK as a novel cancer immunotherapy target, in combination with PD-L1 inhibition, in colorectal cancer and other solid tumours
- Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 2007;26:3279-3290. PMID: 17496922
- Caunt CJ, Sale MJ, Smith PD, Cook SJ. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer. 2015;15:577-592. PMID: 26399658
- Chen D, Heath V, O'Garra A, Johnston J, McMahon M. Sustained activation of the Raf-MEK-ERK pathway elicits cytokine unresponsiveness in T cells. J Immunol. 1999;163:5796-805.
- Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. PMID: 22239440
- Knight T, Irving JA. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front Oncol. 2014;4:160. doi:10.3389/fonc.2014.00160. PMID: 25009801
- Brea EJ, Oh CY, Manchado E, et al. Kinase regulation of human MHC class I molecule expression on cancer cells. Cancer Immunol Res. 2016;4(11):936-947. doi:10.3389/fonc.2014.00160. PMID: 27680026
- de Freitas Saito R, Tortelli TC Jr, Jacomassi MD, Otake AH, Chammas R. Emerging targets for combination therapy in melanomas. FEBS Letters. 2015;589:3438-3448. PMID: 26450371
- Hosler GA, Patterson JW. Lentigines, nevi, and melanomas. In: Patterson JW, ed. Weedon’s Skin Pathology. 4th ed. Philadelphia, PA: Elsevier; 2016:837-902.
- Mimura K, Kua LF, Shiraishi K, et al. Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-γ treatment. Cancer Sci. 2014;105:1236-1244. PMID: 25154680
- Mimura K, Shiraishi K, Mueller A, et al. The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer. J Immunol. 2013;191:6261-6272. PMID: 24244023
- Sers C, Kuner R, Falk CS, et al. Down-regulation of HLA Class I and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells. Int J Cancer. 2009;125:1626-1639. PMID: 19569244
- Inoue M, Mimura K, Izawa S, et al. Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression. Oncoimmunology. 2012;1:1104-1110. PMID: 23170258
- Ebert PJ, Cheung J, Yang Y, et al. MAP kinase inhibition promotes T cell and anti-tumour activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44:609-621. PMID: 26944201
- Chen DS, Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature. 2017;541(7637):321-330. PMID: 28102259
- Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Annals of Oncology. 2016;27:1492-1504. PMID: 27207108
- Chen DS, Mellman I. Oncology meets immunology: the cancer immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
- Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(suppl; abstr 3502).
- Liu L, Mayes PA, Eastman S, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD1, PD-L1 and CTLA-4. Clin Cancer Res. 2015;21:1639-1651. PMID: 25589619
- Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212. PMID: 22236695
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