Multi-organ landscape of therapy-resistant melanoma.
Multi-organ landscape of therapy-resistant melanoma.
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DOI：
10.1038/s41591-023-02304-9
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发表时间：
2023-05
期刊：
影响因子：
82.9
通讯作者：
Lo, Roger S.
中科院分区：
文献类型：
--
作者：
Liu, Sixue;Dharanipragada, Prashanthi;Lomeli, Shirley H.;Wang, Yan;Zhang, Xiao;Yang, Zhentao;Lim, Raymond J.;Dumitras, Camelia;Scumpia, Philip O.;Dubinett, Steve M.;Moriceau, Gatien;Johnson, Douglas B.;Moschos, Stergios J.;Lo, Roger S.
转移和目前治疗的失败是皮肤黑色素瘤患者死亡的最常见原因。为了确定潜在的遗传和转录组学景观，在这项研究中，我们分析了MAPK抑制剂（MAPKi）和/或免疫检查点阻断（ICB）治疗后11例快速尸检的多器官转移和肿瘤相邻组织以及由于获得性耐药导致的死亡。任何一种治疗都可能导致共同的遗传改变，这表明免疫逃避，交叉治疗耐药机制。大的非成簇缺失、倒位和染色体间易位主导重排。分析来自包括345名未经治疗的患者和35名具有患者匹配的治疗前和获得性耐药肿瘤样品的单独的黑色素瘤队列的数据，我们进行了交叉队列分析，以鉴定MAPKi和ICB作为在尸检中与未经治疗的肿瘤相比富集的基因扩增和缺失的各自贡献者。在尸检队列中，私有/晚期突变和结构变体显示出转移的突变和重排特征，MAPKi特异性地选择缺陷性同源重组、错配和碱基切除修复的特征。转录组签名和串扰与肿瘤相邻的宏观环境提名器官特异性适应途径。免疫沙漠，CD 8 +-巨噬细胞偏向的原型，T细胞耗竭和2型免疫的特点是免疫环境。这种对治疗耐药黑色素瘤的多器官分析提出了初步见解，有可能改善治疗策略。在黑色素瘤患者的快速尸检队列研究中进行的基因组分析确定了对MAPK抑制剂和免疫检查点阻断疗法具有获得性耐药性的黑色素瘤的遗传和转录组学景观，为治疗策略的潜在改进提供了见解。
Metastasis and failure of present-day therapies represent the most common causes of mortality in patients with cutaneous melanoma. To identify the underlying genetic and transcriptomic landscapes, in this study we analyzed multi-organ metastases and tumor-adjacent tissues from 11 rapid autopsies after treatment with MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) and death due to acquired resistance. Either treatment elicits shared genetic alterations that suggest immune-evasive, cross-therapy resistance mechanisms. Large, non-clustered deletions, inversions and inter-chromosomal translocations dominate rearrangements. Analyzing data from separate melanoma cohorts including 345 therapy-naive patients and 35 patients with patient-matched pre-treatment and post-acquired resistance tumor samples, we performed cross-cohort analyses to identify MAPKi and ICB as respective contributors to gene amplifications and deletions enriched in autopsy versus therapy-naive tumors. In the autopsy cohort, private/late mutations and structural variants display shifted mutational and rearrangement signatures, with MAPKi specifically selecting for signatures of defective homologous-recombination, mismatch and base-excision repair. Transcriptomic signatures and crosstalks with tumor-adjacent macroenvironments nominated organ-specific adaptive pathways. An immune-desert, CD8+-macrophage-biased archetype, T-cell exhaustion and type-2 immunity characterized the immune contexture. This multi-organ analysis of therapy-resistant melanoma presents preliminary insights with potential to improve therapeutic strategies. Genomic analyses in a rapid autopsy cohort study of patients with melanoma identify the genetic and transcriptomic landscape of melanoma with acquired resistance to MAPK inhibitor and immune checkpoint blockade therapies, providing insights for the potential improvement of therapeutic strategies.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
--
作者：
Budczies J;von Winterfeld M;Klauschen F;Bockmayr M;Lennerz JK;Denkert C;Wolf T;Warth A;Dietel M;Anagnostopoulos I;Weichert W;Wittschieber D;Stenzinger A
通讯作者：
Stenzinger A
影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
64.5
作者：
Hugo W;Shi H;Sun L;Piva M;Song C;Kong X;Moriceau G;Hong A;Dahlman KB;Johnson DB;Sosman JA;Ribas A;Lo RS
通讯作者：
Lo RS