MEK inhibitor

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase 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.)

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

  • Binimetinib (MEK162), approved by the FDA in June 2018 in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[4]
  • Cobimetinib or XL518, approved by US FDA in Nov 2015 for use in combination with vemurafenib (Zelboraf(R)), for treatment of advanced melanoma with a BRAF V600E or V600K mutation.
  • Selumetinib, had a phase 2 clinical trial for non-small cell lung cancer (NSCLC) which demonstrated an improvement in PFS,[5] and is now in phase III development in KRAS mutation positive NSCLC (SELECT-1, NCT01933932). Other ph 3 clinical trials underway include uveal melanoma (failed), and differentiated thyroid carcinoma.
  • Trametinib (GSK1120212), FDA-approved to treat BRAF-mutated melanoma. Also studied in combination with BRAF inhibitor dabrafenib to treat BRAF-mutated melanoma.

In clinical trials

  • PD-325901, for breast cancer, colon cancer, and melanoma[6] A phase II trial for advanced non-small cell lung cancer "did not meet its primary efficacy end point".[7]

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.
  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.
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