Abstract 2981: PM54 targets oncogenic transcriptional networks across multiple cancer types

Abstract Background: PM54, a synthetic ecteinascidin analog derived from lurbinectedin, binds GC-rich promoter regions to block transcription, induce DNA double-strand breaks, and trigger S-phase arrest and apoptosis. We aimed to define PM54 transcriptional mechanisms across tumor types and to identify transcriptomic features associated with heightened sensitivity. Methods: Comprehensive transcriptomic profiling (RNA-seq) was performed following acute PM54 exposure (50 nM, 6 h) in a panel of 32 cancer cell lines representing six tumor types: 12 small-cell lung cancers (SCLC), 8 gastric cancers, 6 prostate cancers, 4 breast cancers, 1 ovarian cancer, and 1 melanoma. Hierarchical clustering, differential expression, GSEA, and GO analyses were used to define temporal transcriptional response clusters. In vivo validation was conducted in four CDX models (SCLC DMS-53, ovarian A2780, melanoma WM-266-4, and TNBC MDA-MB-231) after a single PM54 dose, with RNA-seq performed on day 7. Results: PM54 induced a rapid, broad transcriptional repression in all models, with >2,000 downregulated genes per line and a conserved core of 1,170 commonly repressed genes (versus 226 commonly induced). Repressed programs included cell cycle, RNA Pol II transcription, chromatin organization, DNA repair and MYC targets; early upregulated signatures implicated metabolism, PARP signaling and stress responses. Unsupervised clustering based on PM54 transcriptional effect identified a “primed” responder cluster (characterized by high baseline transcription and rapid transcriptional shutdown after treatment) and an “adaptive” responder cluster. Curiously, all three POU2F3 SCLC lines and prostate cancer models were into the primed responder cluster. Consistently, in vivo transcriptomic analyses recapitulated these clusters, demonstrating enhanced transcriptional repression, MYC/mTOR signaling suppression, and markedly improved survival outcomes in primed (+192%, +345% and +412% in ovarian, melanoma and SCLC, respectively) compared to adaptive responders (+185% in breast cancer and +240% in gastric cancer). Conclusions: PM54 rapidly suppresses proliferative/MYC-driven programs and elicits adaptive metabolic/immune responses. Baseline transcriptional state predicts response and may guide patient selection and combination strategies. Citation Format: Ismael Fernández-Miranda, Javier Robles, Maria José Guillen, Pablo Avilés, Marcelo L. Ribeiro, Carmen Cuevas. PM54 targets oncogenic transcriptional networks across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2981.