The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells
2021
Renata Tisi | Michela Spinelli | Michela Spinelli | Alessandro Palmioli | Cristina Airoldi | Cristina Airoldi | Paolo Cazzaniga | Paolo Cazzaniga | Daniela Besozzi | Daniela Besozzi | Marco S. Nobile | Marco S. Nobile | Elisa Mazzoleni | Simone Arnhold | Luca De Gioia | Luca De Gioia | Rita Grandori | Francesco Peri | Marco Vanoni | Marco Vanoni | Elena Sacco | Elena Sacco
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.
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