Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade

Panayiotis Anastasiou, Christopher Moore, Sareena Rana, Mona Tomaschko, Claire E. Pillsbury, Andrea Castro, Jesse Boumelha, Edurne Mugarza, Sophie Carné Trécesson, Ania Mikolajczak, Cristina Blaj, Robert Goldstone, Jacqueline A. M. Smith, Elsa Quintana, Miriam Molina-Arcas () and Julian Downward ()
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Panayiotis Anastasiou: Francis Crick Institute
Christopher Moore: Francis Crick Institute
Sareena Rana: Francis Crick Institute
Mona Tomaschko: Francis Crick Institute
Claire E. Pillsbury: Francis Crick Institute
Andrea Castro: Francis Crick Institute
Jesse Boumelha: Francis Crick Institute
Edurne Mugarza: Francis Crick Institute
Sophie Carné Trécesson: Francis Crick Institute
Ania Mikolajczak: Francis Crick Institute
Cristina Blaj: Revolution Medicines, Inc.
Robert Goldstone: Francis Crick Institute
Jacqueline A. M. Smith: Revolution Medicines, Inc.
Elsa Quintana: Revolution Medicines, Inc.
Miriam Molina-Arcas: Francis Crick Institute
Julian Downward: Francis Crick Institute

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Mutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RASG12C in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.

Date: 2024
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DOI: 10.1038/s41467-024-52324-3

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