Related Experiment Video

Updated: Jan 12, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

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Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors

Mingming Wu1, Shiyue Yang1, Zhentao Yang1

  • 1Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Immunity
|November 1, 2025
PubMed

Insights

Melanoma patients often relapse after immune checkpoint inhibitor (ICI) therapy. Genomic changes, specifically copy-number variants (CNVs) affecting apoptotic genes, drive acquired resistance. Targeting the apoptotic threshold may prevent melanoma relapse.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • Immune checkpoint inhibitors (ICIs) are effective against melanoma but acquired resistance leads to relapse.
  • Understanding the genomic mechanisms of resistance is crucial for improving long-term patient outcomes.

Purpose of the Study:

  • To investigate the genomic evolution of melanomas that develop resistance to ICIs.
  • To identify potential therapeutic targets to overcome ICI resistance.

Main Methods:

  • Comparative genomic analysis of pretreatment and disease-progressive (DP) melanomas.
  • Derivation of acquired-resistant (AR) melanoma cell lines and murine tumors through chronic exposure to T cells or ICIs.
  • Assessment of apoptotic priming and mitochondrial sensitivity in AR cells.

Main Results:

  • DP melanomas showed recurrent copy-number variants (CNVs) in apoptotic genes.
  • AR cell lines and tumors recapitulated DP CNVs, affecting anti-apoptotic and pro-apoptotic genes.
  • AR melanoma cells exhibited attenuated apoptotic priming, which could be reversed by restoring pro-apoptotic gene expression.
  • Pharmacological reduction of the apoptotic threshold in mice prevented ICI therapy relapses.

Conclusions:

  • CNVs in apoptotic genes drive the evolution of ICI resistance in melanoma.
  • The tumor cell-intrinsic apoptotic threshold is a potential therapeutic target to prevent melanoma persister cell evolution and relapse.
Keywords:
T cell cytotoxicityacquired resistanceanti-CTLA-4anti-PD-1apoptosis sensitivitycopy-number variationgenomic evolutionimmune checkpoint inhibitorimmune evasionmelanomasingle-cell whole-genome sequencingwhole-exome sequencing

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