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Keeping Tumors Out of the MAPK Fitness Zone

David F Stern1

  • 1Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. df.stern@yale.edu.

Cancer Discovery
|January 10, 2018
PubMed

Insights

Tumor cells need balanced MAPK signaling for survival during therapy. New strategies aim to kill cancer cells by manipulating MAPK signaling or preventing resistance with combined BRAF, MEK, and ERK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • MAPK pathway signaling is crucial for tumor cell survival and proliferation.
  • Tumor cell subclones exhibit varying fitness levels during MAPK-targeting therapies.
  • Achieving optimal MAPK pathway signaling is critical for therapeutic success.

Purpose of the Study:

  • To investigate the role of MAPK pathway signaling levels in tumor cell subclone fitness.
  • To explore novel therapeutic strategies for overcoming resistance to MAPK-targeting agents.
  • To identify methods for preventing the selection of resistant cancer clones.

Main Methods:

  • Analysis of tumor cell subclone fitness under different MAPK signaling conditions.
  • Development of therapeutic approaches involving inhibitor withdrawal and DNA damage.
  • Evaluation of triple combination therapy (BRAF, MEK, ERK inhibitors) to impose a fitness barrier.

Main Results:

  • Tumor cell subclones require finely tuned MAPK pathway signaling for maximal fitness.
  • Therapeutic strategies combining inhibitor withdrawal with DNA damage can induce tumor cell death.
  • A triple combination of BRAF, MEK, and ERK inhibitors effectively prevents the selection of resistant clones.

Conclusions:

  • Manipulating MAPK signaling levels is a promising strategy in cancer therapy.
  • Combination therapies can overcome resistance mechanisms in MAPK-targeted treatments.
  • Imposing a steep fitness barrier with triple inhibition is key to preventing therapeutic resistance.

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