MEK inhibitor

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A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. (See MAPK/ERK pathway#Clinical significance.)

Contents

Hence MEK inhibitors have potential for treatment of some cancers, [1] especially BRAF-mutated melanoma, [2] and KRAS/BRAF mutated colorectal cancer. [3]

Approved for clinical use

In clinical trials

Others

Pre-clinical investigation

Clinically approved MEK inhibitor Cobimetinib has been investigated in combination with PI3K inhibition in pre-clinical models of lung cancer, where the combined treatment approach lead to a synergistic anti-cancer response. [9] Co-targeted therapeutic approaches to have been suggested to induce improved anti-cancer effects, due to blockade of compensatory signalling, prevention or delay of acquired resistance to treatment, and the possibility of reducing dosing of each compound. [10] [11]

References

  1. Wang, Ding; Boerner, Scott A.; Winkler, James D.; Lorusso, Patricia M. (2007). "Clinical experience of MEK inhibitors in cancer therapy". Biochim Biophys Acta. 1773 (8): 1248–55. doi: 10.1016/j.bbamcr.2006.11.009 . PMID   17194493.
  2. "ASCO: MEK Inhibitors—Alone or Paired With a BRAF Inhibitor—Increase Options, Benefits for Patients With BRAF-Mutated Advanced Melanoma". 2012.
  3. KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. 2009
  4. Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". www.fda.gov. Retrieved 2018-07-17.[ dead link ]
  5. Jänne, Pasi A; Shaw, Alice T; Pereira, José Rodrigues; Jeannin, Gaëlle; Vansteenkiste, Johan; Barrios, Carlos; Franke, Fabio Andre; Grinsted, Lynda; Zazulina, Victoria; Smith, Paul; Smith, Ian; Crinò, Lucio (2013). "Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study". The Lancet Oncology. 14 (1): 38–47. doi:10.1016/S1470-2045(12)70489-8. PMID   23200175.
  6. MEK Inhibitor PD-325901 To Treat Advanced Breast Cancer, Colon Cancer, And Melanoma
  7. Haura EB, Ricart AD, Larson TG, Stella PJ, Bazhenova L, Miller VA, Cohen RB, Eisenberg PD, Selaru P, Wilner KD, Gadgeel SM (2010). "A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer". Clin Cancer Res. 16 (8): 2450–7. doi:10.1158/1078-0432.CCR-09-1920. PMID   20332327.
  8. MEK inhibitor, TAK-733 reduces proliferation, affects cell cycle and apoptosis, and synergizes with other targeted therapies in multiple myeloma. Feb 2016
  9. Heavey, Susan; Cuffe, Sinead; Finn, Stephen; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin; O'Byrne, Kenneth; Gately, Kathy (2016-11-29). "In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC". Oncotarget. 7 (48): 79526–79543. doi:10.18632/oncotarget.12755. ISSN   1949-2553. PMC   5346733 . PMID   27765909.
  10. Heavey, Susan; O'Byrne, Kenneth J.; Gately, Kathy (April 2014). "Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC". Cancer Treatment Reviews. 40 (3): 445–456. doi:10.1016/j.ctrv.2013.08.006. ISSN   1532-1967. PMID   24055012.
  11. Luszczak, Sabina; Kumar, Christopher; Sathyadevan, Vignesh Krishna; Simpson, Benjamin S.; Gately, Kathy A.; Whitaker, Hayley C.; Heavey, Susan (2020). "PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer". Signal Transduction and Targeted Therapy. 5 7. doi:10.1038/s41392-020-0109-y. ISSN   2059-3635. PMC   6992635 . PMID   32025342.