Targeting the SHOC2–RAS interaction in RAS-mutant cancers
Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer<sup>1</sup>. They have previously been considered undruggable, but advances in the past few years have led to the clinical development of agents that target KRAS(G12C) and KRAS(G12D) mutants, yielding promises of therapeutic responses at tolerated doses<sup>2</sup>. However, clinical agents that selectively target NRAS(Q61*) mutants (* represents 'any'), the second-most-frequent oncogenic driver in melanoma, are still lacking. Here we identify SHOC2, a component of the SHOC2-MRAS-PP1C complex, as a dependency of RAS(Q61*) tumours in a nucleotide-state-dependent and isoform-agnostic manner. Mechanistically, we found that oncogenic NRAS(Q61R) forms a direct interaction with SHOC2, evidenced by X-ray co-crystal structure. In vitro high-throughput screening enabled the discovery of small molecules that bind to SHOC2 and disrupt the interaction with NRAS(Q61*). Structure-based optimization led to a cellularly active tool compound that shows inhibition of mitogen-activated protein kinase (MAPK) signalling and proliferation in RAS-mutant cancer models, most notably in NRAS(Q61*) settings. These findings provide evidence for a neomorph SHOC2-(canonical)RAS protein interaction that is pharmacologically actionable and relevant to cancer sustenance. Overall, this work provides the concept validation and foundation for developing new therapies at the core of the RAS signalling pathway.
Authors
- Giorgio Giacomo Galli (ORCID: https://orcid.org/0000-0002-9401-060X)
- Cornelia Handl (ORCID: https://orcid.org/0009-0003-7248-9028)
- Jean‐Rémy Marchand (ORCID: https://orcid.org/0000-0002-8002-9457)
- Gráinne Kerr (ORCID: https://orcid.org/0009-0004-4231-518X)
- Gregor S. Cremosnik (ORCID: https://orcid.org/0000-0003-3216-5312)
- Anxhela Dhembi
- Carole Pissot‐Soldermann (ORCID: https://orcid.org/0000-0002-7497-3839)
- Danilo Maddalo (ORCID: https://orcid.org/0000-0002-3228-1703)
- Markus Linder (ORCID: https://orcid.org/0000-0003-0696-4444)
- Claudio R. Thoma (ORCID: https://orcid.org/0000-0003-3475-0179)
- Beatrice Faggion
- Kim S. Beyer (ORCID: https://orcid.org/0000-0002-3047-304X)
- Lukas Leder (ORCID: https://orcid.org/0009-0002-4378-6739)
- Sandra Lopez Romero
- Luca Tordella (ORCID: https://orcid.org/0000-0002-0542-7834)
- Travis Stams
- Veronika Ehmke
- Mylene Lanter (ORCID: https://orcid.org/0009-0006-0515-3040)
- Ulrich Hassiepen
- Sandra Mollé
- Zachary J. Hauseman (ORCID: https://orcid.org/0000-0002-0260-2326)
- Jacob P. Brady (ORCID: https://orcid.org/0000-0002-9316-7226)
- Jessica Viscomi (ORCID: https://orcid.org/0000-0003-3607-6325)
- Michelle Fodor
- Frédéric Stauffer
- Sauveur-Michel Maira (ORCID: https://orcid.org/0009-0007-7294-2653)
- Daniel Guthy (ORCID: https://orcid.org/0000-0001-5324-8585)
- Sol Katz (ORCID: https://orcid.org/0009-0006-8730-9351)
- Daniel King (ORCID: https://orcid.org/0000-0003-3319-9733)
- Om Kumar Shrestha
- Daniela Schildknecht
- Zachary Nguyen
- Elena Cavicchioli
Institutions
- Novartis (Switzerland) (CH)
- Novartis (United States) (US)
- Novartis Foundation (CH)
Publication Details
- Journal
- Nature
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1038/s41586-025-08931-1
- Citations
- 15
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 12.09
Funders
- University of Arizona Cancer Center
- Kindai University
- RIKEN
- National Cancer Institute