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Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is

Mariusz L Hartman1, Paulina Koziej1, Katarzyna Kluszczyńska1

  • 1Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland.

Cancers
|October 14, 2023
PubMed
Abstract

Insights

Trametinib resistance in melanoma involves reversible changes in cell signaling and protein levels. Targeting MCL-1 with S63845 effectively induces apoptosis in resistant cells with specific low p-ERK1/2 and MCL-1 phenotypes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • BRAF/MEK inhibitors offer improved melanoma treatment but inevitably lead to acquired resistance.
  • Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate trametinib withdrawal/rechallenge effects in melanoma models.
  • To explore MCL-1 inhibition as a therapeutic strategy in trametinib-resistant melanoma with varying p-ERK1/2 levels.

Main Methods:

  • Studied trametinib withdrawal and rechallenge in melanoma models.
  • Investigated MCL-1 inhibition using the agent S63845 in resistant cell lines.
  • Assessed apoptosis markers including Annexin V, caspase activation, and histone H2AX phosphorylation.

Main Results:

  • Trametinib withdrawal/rechallenge induced reversible alterations in ERK1/2 activity, affecting pro-survival/pro-apoptotic protein balance.
  • MCL-1 levels and inhibitors (BIM, NOXA) showed reversible changes.
  • S63845 effectively induced apoptosis in trametinib-resistant cells with a p-ERK1/2low/MCL-1low/BIMhigh/NOXAlow phenotype, with low EC50 values.
  • Higher ERK1/2 activity, increased MCL-1, and reduced BIM levels limited S63845 efficacy.

Conclusions:

  • Therapeutic agent efficacy depends on cancer cell phenotype.
  • Identifying phenotype determinants is essential for patient stratification in novel melanoma therapies.
Keywords:
MCL-1 inhibitorS63845cancer cell plasticitydrug holidaydrug rechallengemelanomatrametinib resistance

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