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Treatment-Resistant Melanoma Genetic Signatures Emerge From Rapid Autopsy Analysis

NEW YORK — Researchers have uncovered genetic and gene expression changes in the organs of patients who died of precision treatment-resistant metastatic cutaneous melanoma.

The patients had initially benefited from treatments such as MAPK inhibitors (MAPKi) and immune checkpoint blockade (ICB) but later acquired resistance and succumbed to the disease.

Cutaneous melanoma, a cancer that starts in pigment-producing cells, is among the most metastatic cancers. According to the scientists, who published their results in Nature Medicine on Thursday, previous studies did not focus on the effect of treatments such as MAPKi and ICB on the mutational landscape of the tumors.

"We hope to reconstruct, from the end of life, the lethal journey melanoma traverses across time and body sites,” corresponding author Roger Lo, a professor of medicine and molecular and medical pharmacology at the David Geffen School of Medicine at the University of California, Los Angeles, said in a statement.

"We need to know how many ways, even within the same patient, the cancer evades these powerful therapies, what underlying processes create 'new species' capable of escaping therapies, whether the cancer co-opts different organs to help it spread and resist therapies," he added. 

For their study, the researchers focused on patients with two major subtypes of metastatic cutaneous melanoma, harboring mutations in either the BRAF or the NRAS gene, who often have targeted therapy or immune checkpoint blockade as their only options.

The researchers used rapid autopsy to retrieve organs from 11 patients, who had developed resistance to treatments and had gone to hospice, shortly after their deaths and conducted biopsies. 

The samples they analyzed included 71 distinct metastatic tumors, 41 tumor-adjacent "normal" tissues representing organ-specific tumor macroenvironments, and 38 tumor-nonadjacent normal tissues.

Next, they conducted whole-exome and whole-genome sequencing as well as RNA sequencing (RNA-seq) and noted the molecular changes that could have led to treatment resistance. They found 571 significantly amplified and 132 significantly deleted genes in these samples.

Subsequently, they compared the genetic signatures from MAPKi and ICB treatment-resistant samples to cancer samples from the same patients before treatments. This helped them understand how each therapy distinctly shaped mutations, copy number alterations(CNA), and structural variants (SV) in acquired-resistance samples.

"Significantly mutated genes and genes altered by CNAs and SVs enrich in immune-evasive processes … that may confer cross-therapy resistance, accelerating lethal disease progression," the authors wrote.

Findings on patients who had specifically developed MAPKi resistance suggested therapy-elicited DNA damage or deficiency in repair pathways as culprits, the authors noted.

Results on genomic instability, which could be resulting from resistance evolution, have therapeutic implications that warrant mechanistic studies, they added.

Meanwhile, the study also shed light on organ-specific metastatic signatures. Liver and spleen metastases displayed neural differentiation, for example, which the authors wrote suggest therapeutic targets. Brain metastasis, on the other hand, showed signatures of IFN signaling, oxidative phosphorylation, and PI3K-AKT signaling.

"This study puts a sharp focus on alternative strategies to make the cancer visible to our body's anti-tumor immune system," coauthor Stergios Moschos, an associate professor of medicine the University of North Carolina at Chapel Hill, said in a statement.