Genetic Layout of Melanoma Lesions Is Associated with BRAF/MEK-Targeted Therapy Resistance and Transcriptional Profiles

The genetic landscape of melanoma resistance to targeted therapy with small molecules inhibiting BRAF and MEK kinases is still largely undefined. In this study, we portrayed in detail the somatic alterations of resistant melanoma and explored the associated biological processes and their integration with transcriptional profiles. By targeted next-generation sequencing and whole-exome sequencing analyses, a list of 101 genes showing imbalance in metastatic tumors from patients with a complete/durable response or disease progression during therapy with vemurafenib or with dabrafenib and trametinib was defined. 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. Integration of genomic and transcriptomic features showed that the enrichment of mutations in gene sets associated with anabolic processes, chromatin alterations, and IFN-a response determined a significant positive modulation of the same gene signatures at the transcriptional level. In particular, MTORC1 signaling was enriched in tumors from poorly responsive patients and in resistant tumors excised from treated patients. 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.

Automated summary

The genetic landscape of melanoma resistance to targeted therapy with small molecules inhibiting BRAF and MEK kinases was explored in this study. Somatic alterations in resistant melanoma were characterized and their integration with transcriptional profiles revealed enrichment in gene families involved in oncogenic signaling pathways and DNA repair. The analysis also showed positive modulation of gene signatures associated with anabolic processes, chromatin alterations, and IFN-a response. MTORC1 signaling was found to be enriched in poorly responsive patients and resistant tumors. These findings provide insights into the genetic patterns underlying melanoma resistance and have implications for personalized therapies.