AUTHOR=Tisi Renata , Spinelli Michela , Palmioli Alessandro , Airoldi Cristina , Cazzaniga Paolo , Besozzi Daniela , Nobile Marco S. , Mazzoleni Elisa , Arnhold Simone , De Gioia Luca , Grandori Rita , Peri Francesco , Vanoni Marco , Sacco Elena TITLE=The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells JOURNAL=Frontiers in Molecular Biosciences VOLUME=8 YEAR=2021 URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.625979 DOI=10.3389/fmolb.2021.625979 ISSN=2296-889X ABSTRACT=

Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4–previously identified as a water-soluble Ras inhibitor– targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity.