PD-L1 Inhibition + MEK Inhibition

MEK is an emerging target in cancer immunotherapy research

MEK is a signaling molecule in the mitogen-activated protein kinase (MAPK) pathway, which regulates cell growth, proliferation, and differentiation.^1,2

Emerging research has found MEK signaling can also disrupt a key step in the cancer immunity cycle: cancer cell recognition.^3,4

MEK inhibition can increase tumor cell recognition

Targeting MEK may help restore part of the cancer immunity cycle by exposing tumors through increased antigen presentation.^4,5

1. MEK inhibition upregulates major histocompatibility complex (MHC) class 1 expression, which can increase antigen presentation on the surface of tumor cells for recognition by CD8+ T cells
2. T cells are then able to recognize and kill tumor cells*

*Tumor cell killing by CD8+ T cells.

TCR=T-cell receptor. MHC=major histocompatibility complex.

Targeting MEK and PD-L1 may have a synergistic effect on restoring the body's antitumor immune response

Inhibition of the MEK and PD-L1 pathways is a rational approach that may help invigorate T-cell activity against tumor cells.^5,6

Genentech is actively researching the combination of MEK inhibition and PD-L1 inhibition in various tumor types.^7,8

PD-L1=programmed death-ligand 1.

*Tumor cell killing by CD8+ T cells.

References

1. Dhillon AS, Hagan S, Rath O, Kolch W. Oncogene. 2007;26:3279-3290. PMID: 17496922
2. Caunt CJ, Sale MJ, Smith PD, Cook SJ. Nat Rev Cancer. 2015;15:577-592. PMID: 26399658
3. Chen DS, Mellman I. Nature. 2017;541:321-330. PMID: 28102259
4. Brea EJ, Oh CY, Manchado E, et al. Cancer Immunol Res. 2016;4:936-947. PMID: 27680026
5. Ebert PJ, Cheung J, Yang Y, et al. Immunity. 2016;44:609-621. PMID: 26944201
6. Bendell JC, Kim TW, Goh BC, et al. J Clin Oncol. 2016;34.
7. US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02788279. Accessed March 26, 2018.
8. US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02322814. Accessed March 26, 2018.
9. Chen DS, Mellman I. Immunity. 2013;39:1-10. PMID: 23890059