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

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

Foda, Bardees; Baker, Annika; Joachimiak, Lukasz; Mazur, Marzena; Neubig, Richard Rick

DOI:

Abstract

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 inhibitors. It also prevented the development of resistance to (Vem). Here, we investigate the role of 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 (activation of , (PI) staining, and 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 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 cleavage and 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 . Inhibition of or the Rho/MRTF pathway can be employed to prevent melanoma resistance.

Keywords

Melanoma ; Resistance ; RhoGTPases ; caspases ; ; pirin

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