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 can help restore part of the cancer immunity cycle by increasing antigen presentation and tumor cell recognition.4,5

  • MEK inhibition upregulates major histocompatibility complex (MHC) class 1 expression, which can increase the presentation of tumor antigens for recognition by CD8+ T cells
  • T cells are then able to recognize and kill tumor cells 
MEK inhibition leading to tumor cell recognition and killing

TCR=T-cell receptor.

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

MEK inhibition + PD-L1 inhibition restores cancer immunity

PD-L1=programmed death-ligand 1.

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 November 1, 2017.
  8. US National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT02322814. Accessed November 1, 2017.
  9. Chen DS, Mellman I. Immunity. 2013;39:1-10. PMID: 23890059