Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade
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Panos Anastasiou Christopher Moore Sareena Rana Mona Tomaschko Claire E Pillsbury Andrea De Castro Jesse Boumelha Edurne Mugarza Sophie de Carne Ania Mikolajczak Cristina Blaj Robert Goldstone Jacqueline AM Smith Elsa Quintana Miriam Molina Arcas Julian DownwardAbstract
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.
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Journal
Nature Communications
Volume
15
Issue number
1
Pages
8146
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10.1038/s41467-024-52324-3
Europe PubMed Central
39322643
Pubmed
39322643
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The publication was previously a preprint.
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