ERK inhibitors – a valuable new tool for treating RAS/RAF active cancers

It has been found that in half of cell lines with RAS activation mutations the inhibition of ERK1/2 results in growth arrest including those that have acquired resistance to MEK inhibitors [1]. This is important as 50% of patients who are treated with BRAF or MEK inhibitors have disease progression within 6 to 7 months after the initiation of treatment [2].

An ERK1/2 inhibitor may prove effective in combination with MEK/BRAF inhibitors as a “double hit” of the MAPK pathway in RAS/RAF active cancers [3]. The double hit reduces the chances the tumours will spontaneously develop the mutations required to overcome inhibition of the pathway [4].

Novel ERK inhibitors such as Merck’s SCH772984/ MK-8353 or others may well be useful in MAPK combination therapy for melanoma and pancreatic cancer. It should be noted however that a phase I clinical trial of SCH772984/ MK-8353 was terminated by Merck without reason given be it financial or otherwise [5].

Refs

  1. Hayes, Tikvah K., Nicole F. Neel, Chaoxin Hu, Prson Gautam, Melissa Chenard, Brian Long, Meraj Aziz, et al. ‘Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression’. Cancer Cell 29, no. 1 (January 2016): 75–89. doi:10.1016/j.ccell.2015.11.011.
  2. Flaherty, Keith T., Jeffery R. Infante, Adil Daud, Rene Gonzalez, Richard F. Kefford, Jeffrey Sosman, Omid Hamid, et al. ‘Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations’. New England Journal of Medicine 367, no. 18 (November 2012): 1694–1703. doi:10.1056/NEJMoa1210093.
  3. Morris, E. J., S. Jha, C. R. Restaino, P. Dayananth, H. Zhu, A. Cooper, D. Carr, et al. ‘Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors’. Cancer Discovery 3, no. 7 (1 July 2013): 742–50. doi:10.1158/2159-8290.CD-13-0070.
  4. Hatzivassiliou, Georgia, Bonnie Liu, Carol O’Brien, Jill M. Spoerke, Klaus P. Hoeflich, Peter M. Haverty, Robert Soriano, et al. ‘ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors’. Molecular Cancer Therapeutics 11, no. 5 (5 January 2012): 1143–54. doi:10.1158/1535-7163.MCT-11-1010.
  5. ‘A Study of the Safety, Tolerability, and Efficacy of MK-8353 in Participants With Advanced Solid Tumors (MK-8353-001) – Full Text View – ClinicalTrials.gov’. Accessed 27 January 2016. https://clinicaltrials.gov/ct2/show/NCT01358331?term=MK-8353&rank=1.
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