Genetic Patterns, Targeted Therapy Resistance Link in Melanoma Explored in New Study

The analysis could help investigators better understand why a subset of patients with advanced melanoma develops resistance or does not respond to targeted therapy.

A new analysis has revealed a set of genetic patterns that appear to correlate with melanoma resistance to targeted therapy. The study, published in Journal of Investigative Dermatology, could help investigators understand why some patients with melanoma do not respond to treatment and it could lead to better personalized therapies for such patients.

Small-molecule therapies targeting BRAF and MEK kinases have become an important treatment option for patients with advanced metastatic melanoma, but a significant subset of patients do not respond to these therapies and some patients develop resistance leading to relapse.

Yet, the exact reasons why some patients respond poorly to targeted therapy are not well understood, according to the present study authors. Several single genomic events and mutations have been proposed as potential causes of tumor progression despite treatment, but it is unclear if they are the actual drivers of resistance.

“Indications of a common genetic pattern associated with a poor response are lacking, whereas accumulated evidence indicates that resistance may result from nonmutational events occurring in tumor cells or in the tumor microenvironment determining drug tolerance,” the authors said.

There has been limited research into the impact of genetic alterations and nongenetic features related to targeted therapy response in melanoma tumors, the authors said. They therefore decided to retrospectively explore the signaling pathways targeted by the genomic alterations seen in a series of pretherapy metastases among patients who have melanoma. The retrospective nature of the study allowed them to match those characteristics with responses (or lack thereof) to therapy.

“By integrating genetic patterns, obtained by targeted gene sequencing panels and by whole-exome sequencing, with transcriptomic profiles, genomic alterations affecting the regulation of proliferation and survival of melanoma cells were found to be common events associated with resistance to therapy,” they wrote.

The investigators compiled a list of 101 genes with imbalances in the metastatic tumors of patients who had a complete/durable response or who experienced disease progression while receiving either the BRAF V600kinase inhibitor vemurafenib (Zelboraf) or the combination of the BRAF kinase inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist).

“Classification of altered genes in functional categories indicated that the mutational pattern of both resistant tumors and melanoma cell lines was enriched in gene families involved in oncogenic signaling pathways and in DNA repair,” the authors said.

They then compared genomic and transcriptomic features, which suggested that the enrichment of mutations in gene sets linked with anabolic processes, chromatin alterations, and interferon-α response “determined a significant positive modulation of the same gene signatures at the transcriptional level.”

They said MTORC1 signaling was enriched in the tumors of patients with poor responses to therapy and in the excised tumors of patients whose cases were treatment resistant.

“Results indicate that genetic patterns are associated with melanoma resistance to targeted therapy and disclose the underlying key molecular pathways to define drug combinations for improved personalized therapies,” they said.

Reference

Vergani E, Busico A, Dugo M, et al. Genetic layout of melanoma lesions is associated with BRAF/MEK-targeted therapy resistance and transcriptional profiles. J Invest Dermatol. Published online May 26, 2022. doi:10.1016/j.jid.2022.04.027