Explore MEK

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  • Pathway Overview
  • Role In Cancer
  • Targeting MEK
  • Potential of Combinations
Pathway Overview

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
MEK pathway

 

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Role In Cancer

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

MAPK signalling may stop T-cells from recognising and killing tumour cells

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

MEK pathway
MAPK signalling may be associated with T-cell exhaustion and apoptosis at the tumour site

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
Overactive MAPK signalling may prevent the release of tumour-specific antigens

MEK pathway signalling overrides cell death signalling, which may limit the release of tumour antigens.7,8

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Targeting MEK

MEK inhibition may address these mechanisms of immune escape by increasing tumour immunogenicity and enhancing antitumour T-cell activity

MEK inhibition may increase tumour cell recognition

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
MEK pathway
MEK inhibition may lead to intratumoural T-cell accumulation

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
MEK pathway

 

MEK inhibition may lead to intratumoural T-cell activation

Inhibition of MEK signalling may promote cell death by increasing release of tumour-specific antigens.7,8,15

MEK inhibition
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Potential of Combinations

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

Combining inhibition of the MEK and PD-L1 pathways can help reinvigorate T-cell activity in the tumour microenvironment, leading to further propagation of the cancer immunity cycle.13,17,18

 
 
 
 
 
 

Roche is actively investigating MEK as a novel cancer immunotherapy target, in combination with PD-L1 inhibition, in colorectal cancer and other solid tumours

 
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References 
  1. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 2007;26:3279-3290. PMID: 17496922
  2. 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
  3. 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.
  4. 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
  5. 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
  6. 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
  7. 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
  8. Hosler GA, Patterson JW. Lentigines, nevi, and melanomas. In: Patterson JW, ed. Weedon’s Skin Pathology. 4th ed. Philadelphia, PA: Elsevier; 2016:837-902.
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. Chen DS, Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature. 2017;541(7637):321-330. PMID: 28102259
  15. 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
  16. Chen DS, Mellman I. Oncology meets immunology: the cancer immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
  17. 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).
  18. 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
  19. 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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