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Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers.

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journal contribution
posted on 22.07.2022, 09:37 authored by Edurne Mugarza, Febe van Maldegem, Jesse Boumelha, Christopher Moore, Sareena Rana, Miriam Llorian Sopena, Philip East, Rachel Ambler, Panayiotis Anastasiou, Pablo Romero-Clavijo, Karishma Valand, Megan Cole, Miriam Molina-Arcas, Julian Downward
Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harboring KRASG12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRASG12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRASG12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.

Funding

Crick (Grant ID: 10070, Grant title: Downward FC001070) European Research Council (Grant ID: 834692 - RASImmune, Grant title: ERC 834692 - RASImmune) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Wellcome Trust (Grant ID: 103799/A/14/Z, Grant title: WT 103799/A/14/Z)

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