Abstract

The dynamic cellular transitions exhibited by skin cutaneous melanoma (SKCM) cells present a significant challenge to current therapeutic approaches, emphasizing the critical need for innovative treatments. Lurbinectedin, a marine-derived compound belonging to the ecteinascidin family, has recently gained approval for the treatment of metastatic small-cell lung cancer (SCLC). In this study, we demonstrate the efficacy of lurbinectedin against SKCM cells, irrespective of their driver mutations or phenotypic states. Additionally, we have developed two novel derivatives of lurbinectedin, termed ecubectedin and PM54, both of which exhibit potent cytotoxic effects on SKCM cells. Moreover, these analogs demonstrate robust anti-tumor activity in melanoma xenograft models, including those resistant to current therapies, leading to prolonged animal survival. Mechanistically, our investigation reveals that these novel synthetic ecteinascidins markedly suppress oncogenic super-enhancer (SE)-mediated gene expression in SKCM cells through a multifaceted mechanism. They bind to and inhibit the activity of promoters of lineage-specific master transcription factors, as well as promoters of genes encoding ubiquitous transcription factors/coactivators, which are highly enriched at oncogenic SEs. These mechanisms likely synergize to disrupt the expression of cancer-promoting genes. Overall, our findings highlight the potential of synthetic ecteinascidins as promising therapeutics for cancers characterized by diverse transcriptional landscapes, particularly in cases where conventional therapeutic options have failed due to the heterogeneity of malignant cell population