2. Academic Validation
  3. Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade

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

  • Nat Commun. 2024 Sep 25;15(1):8146. doi: 10.1038/s41467-024-52324-3.
Panayiotis Anastasiou 1,  Christopher Moore 1,  Sareena Rana 1,  Mona Tomaschko 1,  Claire E Pillsbury 1,  Andrea de Castro 1,  Jesse Boumelha 1,  Edurne Mugarza 1,  Sophie de Carné Trécesson 1,  Ania Mikolajczak 2,  Cristina Blaj 3,  Robert Goldstone 4,  Jacqueline A M Smith 3,  Elsa Quintana 3,  Miriam Molina-Arcas 5,  Julian Downward 6
Affiliations

Affiliations

  • 1 Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
  • 2 Experimental Histopathology, Francis Crick Institute, London, UK.
  • 3 Revolution Medicines, Inc., Redwood City, CA, USA.
  • 4 Bioinformatics & Biostatistics Science Technology Platform, Francis Crick Institute, London, UK.
  • 5 Oncogene Biology Laboratory, Francis Crick Institute, London, UK. miriam.molina@crick.ac.uk.
  • 6 Oncogene Biology Laboratory, Francis Crick Institute, London, UK. julian.downward@crick.ac.uk.
PMID: 39322643 DOI: 10.1038/s41467-024-52324-3
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.93%, KRAS G12C Inhibitor
    Ras