Abstract LB232: Deciphering novel MRTF-A inhibitors and combination strategies for HCC therapy

Abstract Myocardin-related transcription factor A (MRTF-A) is a coactivator of the transcription factor serum response factor (SRF) that promotes the expression of genes involved in cell proliferation, migration and differentiation and triggers HCC progression. Therapeutic knockdown of MRTF-A induces senescence and quiescence in HCC xenografts and may be harnessed as a novel molecularly targeted strategy for the treatment of HCCs and recurrent disease. We recently demonstrated that the negative gating modulator NS8593 of the transient receptor potential cation channel TRPM7 inhibits MRTF-A by promoting its nuclear export. We generated derivatives of NS8593, which are more potent in inhibiting SRF transcriptional activity, as determined by reporter gene assays. Remarkably, we assessed MRTF-A nuclear localization by Fluorescence Loss in Photobleaching (FLIP) to define responsiveness to the novel MRTF inhibitors. Upon administration of the improved NS8593 analogs, nuclear export of MRTF-A was increased and the expression of the MRTF/SRF target genes such as transforming growth factor β1 (TGF-β1) and tetraspanin 5 (TSPAN5) was significantly reduced, resulting in senescence induction and proliferation arrest in HCC cells. Our novel MRTF inhibitors highlight the therapeutic potential of targeting this pathway, also in combination therapies with receptor tyrosine kinase inhibitors. Thus, our studies illuminate for the first time the potential of combining MRTF-A inhibitors with established therapies to combat HCC growth and drug resistance. Citation Format: Miriam Jasmin Franz, Laura Rupprecht, Pia Wenisch, Petra Wohlleben, Vladimir Chubanov, Thomas Gudermann, Salla Kyheröinen, Achim Aigner, Maria Kristina Vartiainen, Markus Heinrich, Susanne Mühlich. Deciphering novel MRTF-A inhibitors and combination strategies for HCC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB232.