Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade.
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Embargo End Date
ICR Authors
Authors
Anastasiou, P
Moore, C
Rana, S
Tomaschko, M
Pillsbury, CE
de Castro, A
Boumelha, J
Mugarza, E
de Carné Trécesson, S
Mikolajczak, A
Blaj, C
Goldstone, R
Smith, JAM
Quintana, E
Molina-Arcas, M
Downward, J
Moore, C
Rana, S
Tomaschko, M
Pillsbury, CE
de Castro, A
Boumelha, J
Mugarza, E
de Carné Trécesson, S
Mikolajczak, A
Blaj, C
Goldstone, R
Smith, JAM
Quintana, E
Molina-Arcas, M
Downward, J
Document Type
Journal Article
Date
2024-09-25
Date Accepted
2024-09-03
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.
Citation
Nature Communications, 2024, 15 (1), pp. 8146 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Lung Cancer Group