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Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer

Matthew J Sale1, Simon J Cook1

  • 1*Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.

Biochemical Society Transactions
|August 12, 2014
PubMed

Insights

Targeting the RAF-MEK1/2-ERK1/2 pathway with BRAF and MEK inhibitors shows cancer treatment promise. However, limited patient response and acquired resistance necessitate understanding resistance mechanisms and pathway feedback for improved efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • BRAF and MEK1/2 inhibitors target the RAF-MEK1/2-ERK1/2 signaling cascade, showing potential in cancer therapy.
  • Clinical responses to these inhibitors are limited, with acquired resistance developing over time.

Purpose of the Study:

  • To review mechanisms of intrinsic and acquired resistance to MEK1/2 inhibitors.
  • To discuss recent advances in understanding pathway feedback influencing MEK1/2 inhibitor activity.

Main Methods:

  • Review of in vitro studies identifying resistance mechanisms.
  • Analysis of clinical data on BRAF and MEK1/2 inhibitor efficacy and resistance.
  • Discussion of pathway feedback loops affecting inhibitor activity.

Main Results:

  • In vitro studies have identified multiple mechanisms of resistance to MEK1/2 inhibitors.
  • These resistance mechanisms often mirror those observed in clinical settings.
  • Pathway feedback significantly influences the activity of MEK1/2 inhibitors.

Conclusions:

  • Understanding resistance mechanisms and pathway feedback is crucial for overcoming therapeutic limitations of BRAF and MEK1/2 inhibitors.
  • Further research into these areas may lead to improved treatment strategies for cancers targeted by these inhibitors.

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