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BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers

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Abstract

The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in-depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance.

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Authors and Affiliations

  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Jaquelyn N. Sanchez & Mark S. Cohen

  2. Department of Surgery, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, USA

    Ton Wang & Mark S. Cohen

Authors
  1. Jaquelyn N. Sanchez
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  2. Ton Wang
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  3. Mark S. Cohen
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Correspondence to Mark S. Cohen.

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Funding

The authors would like to acknowledge the following sources of funding that supported in part the work and effort completed on the manuscript. These include funding from the Department of Surgery at the University of Michigan (MSC and TW) as well as grant funding from the National Institute of Health (R01CA120458 and R01CA216919—MSC) and (T32GM007767—JNS).

Conflict of interest

MSC has received consulting fees from EEPI and Acousys Biomedical Devices LLC in the last year—unrelated to the current manuscript. He is cofounder of NanoPharm LLC, and MedGuider LLC and currently serves as CEO of MedGuider. He has ownership interest in both companies, but no royalties have been generated from either company and neither company is related at all to the topic in the manuscript. The other authors declare no conflict of interest.

Additional information

Jaquelyn N. Sanchez and Ton Wang contributed equally to this manuscript.

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Sanchez, J.N., Wang, T. & Cohen, M.S. BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. Drugs 78, 549–566 (2018). https://doi.org/10.1007/s40265-018-0884-8

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