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Melanoma pp 165-179 | Cite as

Principles of Targeted Therapy

  • Gideon BollagEmail author
  • Keith T. Flaherty
Reference work entry

Abstract

With the increasing volume of genetic melanoma profiling, key oncogenic driver mutations have attracted substantial attention as therapeutic targets. Chief among these are BRAF and KIT. Since BRAF mutations occur in about half of all melanomas, BRAF pathway inhibition has attracted the bulk of therapeutic attention. The discovery of BRAF mutations in cutaneous melanomas led to considerable research into the role of BRAF/MEK/ERK signaling and its role in melanomagenesis. In parallel, drug discovery efforts targeting BRAF, MEK, and ERK led to promising therapeutic candidates. Single-agent BRAF inhibitors showed strong efficacy in metastatic melanoma patients, effectively transforming the treatment for BRAF-mutant cutaneous melanoma patients. MEK inhibitors also showed efficacy as single agents, but the combination of BRAF and MEK inhibitors was clearly superior to either single-agent treatment. ERK inhibitors are currently undergoing clinical development. KIT mutations are primarily found in acral and mucosal melanomas, and several KIT inhibitors have been tested in KIT-mutant melanoma clinical trials; so far none have been approved by regulatory agencies. The challenge for KIT inhibitors may lie in the rarity and diversity of KIT genetic mutations. This chapter explores the biology of BRAF- and KIT-mutant melanoma cells and describes discovery of therapeutic candidates and reviews their role in clinical care.

Keywords

BRAF KIT MEK ERK Resistance RAF inhibitor paradox 

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Plexxikon Inc.BerkeleyUSA
  2. 2.Henri and Belinda Termeer Center for Targeted TherapiesMGH Cancer CenterCambridgeUSA

Section editors and affiliations

  • David E. Fisher
    • 1
  • Nick Hayward
    • 2
  • David C. Whiteman
    • 3
  • Keith T. Flaherty
    • 4
  • F. Stephen Hodi
    • 5
    • 6
  • Hensin Tsao
    • 7
    • 8
  • Glenn Merlino
    • 9
  1. 1.Department of Dermatology, Harvard/MGH Cutaneous Biology Research Center, and Melanoma Program, MGH Cancer CenterMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.QIMR Berghofer Medical Research InstituteHerstonAustralia
  3. 3.QIMR Berghofer Medical Research InstituteHerstonAustralia
  4. 4.Henri and Belinda Termeer Center for Targeted TherapiesMGH Cancer CenterBostonUSA
  5. 5.FraminghamUSA
  6. 6.Department of Medicine, Brigham and Women's HospitalDana-Farber Cancer InstituteBostonUSA
  7. 7.AuburndaleUSA
  8. 8.Harvard-MIT Health Sciences and TechnologyCambridgeUSA
  9. 9.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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