Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy.

IF 13.3 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2026-09-11 Epub Date: 2026-08-20 DOI:10.1016/j.medj.2026.101266

Andrew D Knight, Emily J Robitschek, Jia-Ren Lin, Tyler Aprati, Giuseppe Tarantino, Jaijia Chen, Dennie T Frederick, Alvin Shi, Ana B Larque, Benchun Miao, Rumya S Raghavan, Tatyana Sharova, John H Shin, Peter Sorger, Manolis Kellis, Keith T Flaherty, Nir Hacohen, Genevieve M Boland, Ivan Chebib, David Liu, Ryan J Sullivan, Arnav Mehta

{"title":"Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy.","authors":"Andrew D Knight, Emily J Robitschek, Jia-Ren Lin, Tyler Aprati, Giuseppe Tarantino, Jaijia Chen, Dennie T Frederick, Alvin Shi, Ana B Larque, Benchun Miao, Rumya S Raghavan, Tatyana Sharova, John H Shin, Peter Sorger, Manolis Kellis, Keith T Flaherty, Nir Hacohen, Genevieve M Boland, Ivan Chebib, David Liu, Ryan J Sullivan, Arnav Mehta","doi":"10.1016/j.medj.2026.101266","DOIUrl":null,"url":null,"abstract":"Background: Acquired resistance to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of metastatic melanoma. Phenotypic plasticity, such as dedifferentiation and transdifferentiation, is an increasingly recognized mechanism of treatment resistance.Methods: We present a case of a 70-year-old man with metastatic melanoma who experienced progression through sequential treatments including pembrolizumab in combination with the HDAC inhibitor entinostat and ipilimumab. During treatment, a histologically distinct pleomorphic rhabdomyosarcoma (RMS) emerged at metastatic sites. Longitudinally acquired tumor samples representing both phenotypes were analyzed using whole-exome sequencing (WES), RNA sequencing (RNA-seq), and high-plex tissue imaging (spatial proteomics).Findings: WES revealed driver mutations (e.g., NRAS and NF1) and loss of heterozygosity (LOH) shared between phenotypes indicating a common ancestral clone. Phylogenetic analysis demonstrated an early divergence of the phenotypes, with each later acquiring unique mutations. RNA-seq showed mutually exclusive expression of lineage-specific markers as well as epithelial-mesenchymal transition and myogenic gene set enrichment in the RMS samples. High-plex imaging identified distinct tumor microenvironments, with RMS lesions enriched in CD163+ macrophages.Conclusions: This case provides molecular evidence of phenotypic plasticity occurring under the selective pressure of immune checkpoint inhibitor therapy.Funding: This study was supported by the National Institutes of Health (K12CA087723 and K08CA234458), the Doris Duke Charitable Foundation, and Adelson Medical Research Foundation.","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101266"},"PeriodicalIF":13.3000,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2026.101266","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/8/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Acquired resistance to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of metastatic melanoma. Phenotypic plasticity, such as dedifferentiation and transdifferentiation, is an increasingly recognized mechanism of treatment resistance.

Methods: We present a case of a 70-year-old man with metastatic melanoma who experienced progression through sequential treatments including pembrolizumab in combination with the HDAC inhibitor entinostat and ipilimumab. During treatment, a histologically distinct pleomorphic rhabdomyosarcoma (RMS) emerged at metastatic sites. Longitudinally acquired tumor samples representing both phenotypes were analyzed using whole-exome sequencing (WES), RNA sequencing (RNA-seq), and high-plex tissue imaging (spatial proteomics).

Findings: WES revealed driver mutations (e.g., NRAS and NF1) and loss of heterozygosity (LOH) shared between phenotypes indicating a common ancestral clone. Phylogenetic analysis demonstrated an early divergence of the phenotypes, with each later acquiring unique mutations. RNA-seq showed mutually exclusive expression of lineage-specific markers as well as epithelial-mesenchymal transition and myogenic gene set enrichment in the RMS samples. High-plex imaging identified distinct tumor microenvironments, with RMS lesions enriched in CD163⁺ macrophages.

Conclusions: This case provides molecular evidence of phenotypic plasticity occurring under the selective pressure of immune checkpoint inhibitor therapy.

Funding: This study was supported by the National Institutes of Health (K12CA087723 and K08CA234458), the Doris Duke Charitable Foundation, and Adelson Medical Research Foundation.

查看原文本刊更多论文

黑色素瘤到横纹肌肉瘤的可塑性在免疫治疗的设置。

背景：对免疫检查点抑制剂（ICIs）的获得性耐药仍然是转移性黑色素瘤治疗中的一个重大挑战。表型可塑性，如去分化和转分化，是一种越来越被认可的治疗抗性机制。方法：我们报告了一例70岁男性转移性黑色素瘤患者，他通过序贯治疗，包括派姆单抗联合HDAC抑制剂恩替诺他和伊匹单抗，经历了进展。在治疗期间，组织学上明显的多形性横纹肌肉瘤（RMS）出现在转移部位。采用全外显子组测序（WES）、RNA测序（RNA-seq）和高plex组织成像（空间蛋白质组学）对纵向获得的两种表型的肿瘤样本进行分析。结果：WES揭示了驱动突变（例如NRAS和NF1）和表型之间共享的杂合性（LOH）缺失，表明共同的祖先克隆。系统发育分析证明了表型的早期分化，每个表型后来获得独特的突变。RNA-seq显示，在RMS样品中，谱系特异性标记、上皮-间质转化和肌源性基因集的表达是互斥的。高复合成像发现了不同的肿瘤微环境，RMS病变中富含CD163+巨噬细胞。结论：本病例提供了在免疫检查点抑制剂治疗的选择性压力下发生表型可塑性的分子证据。本研究由美国国立卫生研究院（K12CA087723和K08CA234458）、Doris Duke慈善基金会和Adelson医学研究基金会支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.