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Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma

Pietro Carotenuto1, Alessia Romano2, Anna Barbato2

  • 1TIGEM, Telethon Institute of Genetics and Medicine, 80078 Naples, Italy; Department of Translational Medical Science, University of Naples "Federico II", 80131 Naples, Italy.

Cell Reports
|November 9, 2022
PubMed

Insights

Researchers identified the MITF/APAF-1 axis as key to melanoma's resistance to MAPK inhibitors. New drugs, quinacrine and methylbenzethonium, target this axis, showing promise for treating resistant melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Melanoma exhibits significant resistance to MAPK inhibitor therapies.
  • Understanding the molecular mechanisms driving this resistance is crucial for developing effective treatments.

Purpose of the Study:

  • To identify molecular drivers of MAPK inhibitor resistance in melanoma.
  • To discover novel therapeutic strategies targeting resistant melanoma.

Main Methods:

  • Transcriptome analysis of sensitive and resistant melanoma.
  • Drug-repositioning screen to identify apoptosis-inducing compounds.
  • In vitro and in vivo validation of anti-tumor activity.
  • Analysis of drug effects on signaling networks and epigenetic modulators.

Main Results:

  • APAF-1 is negatively regulated by MITF in resistant melanoma, forming the MITF/APAF-1 axis.
  • Quinacrine and methylbenzethonium activate apoptosis and suppress MITF function.
  • These compounds demonstrate anti-tumor activity in vitro and in vivo.
  • Drugs sensitize melanoma cells to MAPK inhibitors by targeting the MITF/APAF-1 axis and epigenetic modulators like histone deacetylases.

Conclusions:

  • The MITF/APAF-1 axis is a critical driver of MAPK inhibitor resistance in melanoma.
  • Targeting this axis with quinacrine and methylbenzethonium represents a potential therapeutic strategy for resistant melanoma.
  • These drugs may overcome therapy resistance by modulating key signaling and epigenetic pathways.
Keywords:
CP: Cancermelanoma drug resistance, MAPK inhibitors, drug repositioning, MITF, APAF-1, epigenetic drugs, apoptosome, drug repositioning, apoptosome-independent cell death

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