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Multi-organ landscape of therapy-resistant melanoma.
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.
Afiliação
  • Liu S; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Dharanipragada P; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lomeli SH; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Wang Y; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Zhang X; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Yang Z; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lim RJ; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Dumitras C; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Scumpia PO; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Dubinett SM; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Moriceau G; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Johnson DB; Department of Dermatology, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
  • Moschos SJ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lo RS; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Med ; 29(5): 1123-1134, 2023 05.
Article em En | MEDLINE | ID: mdl-37106167
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Melanoma Tipo de estudo: Observational_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Melanoma Tipo de estudo: Observational_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article