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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1505000

Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: Implications for the involvement of pirin

Provisionally accepted
Bardees M Foda Bardees M Foda 1*Annika E Baker Annika E Baker 1Łukasz Joachimiak Łukasz Joachimiak 2Marzena Mazur Marzena Mazur 2Richard R Neubig Richard R Neubig 1*
  • 1 Michigan State University, East Lansing, United States
  • 2 Molecure AA, Warsaw, Poland

The final, formatted version of the article will be published soon.

    Aim: Overcoming therapy resistance is critical for effective melanoma control. Upregulation of Rho/MRTF signaling in human and mouse melanomas causes resistance to targeted therapies. Inhibition of this pathway by MRTFi, CCG-257081 resensitized resistant melanomas to BRAF and MEK inhibitors. It also prevented the development of resistance to vemurafenib (Vem). Here, we investigate the role of apoptosis and the protein pirin in CCG-257081-mediated suppression of drug resistance. Methods: Using naïve and resistant mouse YUMMER melanoma cells, we studied the effect of the BRAF inhibitor Vem with or without CCG-257081 on real-time growth and apoptosis (activation of caspase, Propidium iodide (PI) staining, and PARP cleavage). The effects of CCG-257081 on proliferation (Ki67) and caspase-3 activation were assessed in resistant YUMMER_R tumors in vivo. Finally, two CCG-257081 enantiomers were tested for pirin binding, inhibition of the Rho/MRTF-mediated activation of ACTA2 gene expression in fibroblasts, and the prevention of Vem resistance development by YUMMER_P cells. Results: Vem reduced growth of parental but not resistant cells, while CCG-257081 inhibited both. The combination was more effective than Vem alone. CCG-257081, but not Vem, induced activation of caspase-3 and -7 in resistant cells and increased PARP cleavage and PI staining. CCG-257081 reduced proliferation and activated caspase-3 in YUMMER_R melanoma tumors. Both CCG-257081 enantiomers robustly suppressed development of Vem-resistant colonies with the S isomer being more potent (1 µM IC50). Conclusion: CCG-257081 appears to target pre-resistant cells and Vem-induced resistant cells through enhanced apoptosis. Inhibition of pirin or the Rho/MRTF pathway can be employed to prevent melanoma resistance.

    Keywords: Melanoma, Drug Resistance, Apoptosis, Rho/MRTF, Pirin Melanoma, Resistance, RhoGTPases, Caspases

    Received: 01 Oct 2024; Accepted: 08 Jan 2025.

    Copyright: © 2025 Foda, Baker, Joachimiak, Mazur and Neubig. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Bardees M Foda, Michigan State University, East Lansing, United States
    Richard R Neubig, Michigan State University, East Lansing, United States

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