Multi-organ landscape of therapy-resistant melanoma

Sixue Liu; Prashanthi Dharanipragada; Shirley H Lomeli; Yan Wang; Xiao Zhang; Zhentao Yang; Raymond J Lim; Camelia Dumitras; Philip O Scumpia; Steve M Dubinett; Gatien Moriceau; Douglas B Johnson; Stergios J Moschos; Roger S Lo

doi:10.1038/s41591-023-02304-9

Multi-organ landscape of therapy-resistant melanoma

Nat Med. 2023 May;29(5):1123-1134. doi: 10.1038/s41591-023-02304-9. Epub 2023 Apr 27.

Authors

Sixue Liu¹, Prashanthi Dharanipragada^#¹, Shirley H Lomeli^#¹, Yan Wang^#^{1

2}, Xiao Zhang^#¹, Zhentao Yang¹, Raymond J Lim³, Camelia Dumitras³, Philip O Scumpia^{1

4

5}, Steve M Dubinett^{2

3

4}, Gatien Moriceau¹, Douglas B Johnson^{6

7}, Stergios J Moschos^{8

9}, Roger S Lo^{10

11

12}

Affiliations

¹ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
³ 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.
⁴ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Dermatology, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁶ Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Division of Medical Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. rlo@mednet.ucla.edu.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. rlo@mednet.ucla.edu.
¹² Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. rlo@mednet.ucla.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Drug Resistance, Neoplasm / genetics
Gene Expression Profiling
Humans
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / pathology
Skin Neoplasms* / drug therapy
Skin Neoplasms* / genetics
Transcriptome / genetics

Abstract

Publication types

MeSH terms

Grants and funding