Targeting the SHOC2–RAS interaction in RAS-mutant cancers

Zachary J. Hauseman, Frédéric Stauffer, Kim S. Beyer, Sandra Mollé, Elena Cavicchioli, Jean-Remy Marchand, Michelle Fodor, Jessica Viscomi, Anxhela Dhembi, Stéphanie Katz, Beatrice Faggion, Mylene Lanter, Grainne Kerr, Daniela Schildknecht, Cornelia Handl, Danilo Maddalo, Carole Pissot Soldermann, Jacob Brady, Om Shrestha, Zachary Nguyen, Lukas Leder, Gregor Cremosnik, Sandra Lopez Romero, Ulrich Hassiepen, Travis Stams, Markus Linder, Giorgio G. Galli, Daniel A. Guthy, Daniel A. King, Sauveur-Michel Maira, Claudio R. Thoma, Veronika Ehmke () and Luca Tordella ()
Additional contact information
Zachary J. Hauseman: Novartis BioMedical Research
Frédéric Stauffer: Novartis BioMedical Research
Kim S. Beyer: Novartis BioMedical Research
Sandra Mollé: Novartis BioMedical Research
Elena Cavicchioli: Novartis BioMedical Research
Jean-Remy Marchand: Novartis BioMedical Research
Michelle Fodor: Novartis BioMedical Research
Jessica Viscomi: Novartis BioMedical Research
Anxhela Dhembi: Novartis BioMedical Research
Stéphanie Katz: Novartis BioMedical Research
Beatrice Faggion: Novartis BioMedical Research
Mylene Lanter: Novartis BioMedical Research
Grainne Kerr: Novartis BioMedical Research
Daniela Schildknecht: Novartis BioMedical Research
Cornelia Handl: Novartis BioMedical Research
Danilo Maddalo: Novartis BioMedical Research
Carole Pissot Soldermann: Novartis BioMedical Research
Jacob Brady: Novartis BioMedical Research
Om Shrestha: Novartis BioMedical Research
Zachary Nguyen: Novartis BioMedical Research
Lukas Leder: Novartis BioMedical Research
Gregor Cremosnik: Novartis BioMedical Research
Sandra Lopez Romero: Novartis BioMedical Research
Ulrich Hassiepen: Novartis BioMedical Research
Travis Stams: Novartis BioMedical Research
Markus Linder: Novartis BioMedical Research
Giorgio G. Galli: Novartis BioMedical Research
Daniel A. Guthy: Novartis BioMedical Research
Daniel A. King: Novartis BioMedical Research
Sauveur-Michel Maira: Novartis BioMedical Research
Claudio R. Thoma: Novartis BioMedical Research
Veronika Ehmke: Novartis BioMedical Research
Luca Tordella: Novartis BioMedical Research

Nature, 2025, vol. 642, issue 8066, 232-241

Abstract: Abstract Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer1. 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 doses2. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08931-1

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