Evidence map›Paper›PMID 41175874›Full record

ArticleImmunity2025

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

Mingming Wu, Shiyue Yang, Zhentao Yang, Jian Fan, Shirley H Lomeli, Prashanthi Dharanipragada, Gatien Moriceau, Robert Damoiseaux, Mark C Kelley, Carlos N Prieto-Granada and 7 more

Abstract read

PubMed Full text at PMC Publisher

In one paragraph

Article in Immunity, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it

0cells of the map it votes in

6citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

Overcoming melanoma drug resistance: Mechanisms and clinical progress of oncolytic viruses combined with immune checkpoint inhibitors (Review).Oncology reports · 2026
Review
Chromosome Microarray Analysis of 3832 Patients over 15 Years Confirms Genome-Wide Copy Number Variation in Patients with Developmental Disabilities Including Autism.Current issues in molecular biology · 2026
Article
Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.Nature communications · 2026
Article
Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.bioRxiv : the preprint server for biology · 2026
Article
A novel prenylflavonoid with efficacy in cancer therapy by targeting ceramide-orchestrated signaling.Frontiers in pharmacology · 2026
Article
Evolution from KRAS G12C-mutant to ALK fusion-positive stage IV lung adenocarcinoma following immune checkpoint inhibitor therapy: a case report.Frontiers in oncology · 2026
Article

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Mingming WuDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Shiyue YangDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Zhentao YangDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Jian FanDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Shirley H LomeliDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Prashanthi DharanipragadaDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Gatien MoriceauDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Robert DamoiseauxDepartment of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.

Mark C KelleyDepartment of General Surgery, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Carlos N Prieto-GranadaVanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.

Alessio GiubellinoDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

Mehdi NosratiCenter for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco, CA, USA; California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Mohammed Kashani-SabetCenter for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco, CA, USA; California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Kevin B KimCenter for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco, CA, USA; California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Douglas B JohnsonVanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Sixue LiuDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Roger S LoDivision of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: rlo@mednet.ucla.edu.

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Robert Damoiseaux · 1985 to 2026

$134.5M

Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor: Immunotherapy Combinations (ST-Analytics)U54CA274509 · NCI · INSTITUTE FOR SYSTEMS BIOLOGY · PI Claudia Ludwig · 2022 to 2026

$15.6M

TARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMASP01CA168585 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI RIBAS, ANTONI · 2013 to 2017

$8.4M

Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistanceR01CA176111 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROGER S LO · 2013 to 2026

$5.4M

Melanoma Resistance Evolution Atlas (MREA) for identifying combinatorial targets to prevent and reverse MAPKi resistanceR01CA282198 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROGER S LO, Alan Tackett · 2024 to 2026

$2.0M

NCI NIH HHS P01 CA168585NCI NIH HHS P30 CA016042NCI NIH HHS R01 CA176111NCI NIH HHS R01 CA282198NCI NIH HHS U54 CA274509

6 · The paper itself

Abstract

Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.

Indexed as

ApoptosisDNA Copy Number VariationsDrug Resistance, NeoplasmImmune Checkpoint InhibitorsMelanomaAnimalsCell Line, TumorHumansMiceTumor EscapeImmune Checkpoint Inhibitorsacquired resistanceanti-CTLA-4anti-PD-1apoptosis sensitivitycopy-number variationgenomic evolutionimmune checkpoint inhibitorimmune evasionmelanomasingle-cell whole-genome sequencingT cell cytotoxicitywhole-exome sequencing

Identifiers

PMID41175874

DOI10.1016/j.immuni.2025.10.001

PMCPMC12693071

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