The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

Renata Tisi, Michela Spinelli, Alessandro Palmioli, Cristina Airoldi, Paolo Cazzaniga, Daniela Besozzi, Marco S. Nobile, Elisa Mazzoleni, Simone Arnhold, Luca De Gioia, Rita Grandori, Francesco Peri, Marco Vanoni, Elena Sacco (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number625979
Number of pages15
JournalFrontiers in Molecular Biosciences
Volume8
DOIs
Publication statusPublished - 17 Feb 2021

Keywords

  • anti-cancer agent
  • cetuximab
  • exchange factor
  • intrinsic nucleotide dissociation and exchange
  • mathematical modeling & simulation
  • Raf1 binding
  • RasG12V
  • RasG13D

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