Abstract 1773: PM54, a novel transcription inhibitor with promising broad-spectrum antitumor activity

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PM54, a novel synthetic member of the ecteinascidin family, is derived from lurbinectedin, a marine-derived compound recognized for its potential in cancer therapy. This study aimed to characterize the in vitro antitumor activity of PM54, elucidate its mechanism of action through transcriptomic profiling and validate its antitumor efficacy in vivo. The antineoplastic activity of PM54 was assessed using a panel of 37 cancer cell lines representative of breast, gastric, melanoma, ovary, small cell lung cancer (SCLC), and prostate cancers through MTT assays. Cell cycle analysis, as well as apoptosis assessment, were both performed after a 24-h incubation period with PM54 at 50 nM by FACS. DNA binding capacity was assessed using electrophoretic mobility shift, DNase I footprinting and FRET-based assays, with further interaction mode evaluation by X-ray analysis. 3H-uridine incorporation assays were conducted to measure mRNA synthesis. RNA-seq was used to analyze gene signatures associated with 6-h of incubation with 50 nM of PM54. The in vivo antitumor efficacy of PM54 was characterized in relevant xenograft models of breast, gastric, melanoma, ovary, SCLC, and prostate cancers. PM54 exhibits potent in vitro antitumor activity, with mean GI50 values in the low nanomolar range. It exhibits a strong covalent binding affinity for specific DNA triplets, particularly those with guanine in the second position and either guanine or cytosine in the third position. Mechanistically, PM54 inhibits mRNA synthesis by causing the stalling and proteasomal degradation of RNA Polymerase II. This disruption results in double-strand DNA breaks, S-phase cell cycle arrest, and ultimately culminates in apoptotic cell death. RNA-seq analysis revealed that PM54 robustly downregulates genes associated with cell cycle regulation, key signaling pathways (WNT, MAPK, NOTCH, ERBB) and DNA damage response, including homologous recombination repair. Weekly intravenous (i.v.) administration of PM54 at its maximum tolerated dose (MTD) demonstrated significant antitumor activity and survival benefits across multiple preclinical tumor models, including breast, melanoma, gastric, ovarian, SCLC, and prostate. Tumor reduction and survival improvements were statistically significant in all models, with p-values ranging from 0.0002 to <0.0001. Median overall survival (OS) times in PM54-treated groups were markedly longer than in controls, highlighting PM54’s potential as an effective therapeutic agent. In conclusion, PM54 demonstrates robust antitumor effects across various cancers by impairing mRNA synthesis and inducing DNA damage, underscoring its therapeutic promise. Citation Format: Marta M. Diez, Gema Santamaría Nuñez, Tommy Darriere, Federico M. Ruiz, Carlos Fernández-Tornero, Ismael Fernández-Miranda, Maria José Guillen, Pablo M. Avilés, Marcelo Lima Ribeiro, Carmen Cuevas. PM54, a novel transcription inhibitor with promising broad-spectrum antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1773.

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