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

MEK inhibition + PD-L1 inhibition restores cancer immunity

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