Therapeutic strategies to promote immune rejection of drug-resistant sub-populations in lung cancer
File(s)
Author(s)
Tomaschko, Mona
Type
Thesis
Abstract
KRAS is the most frequently mutated oncogene in human cancer. Oncogenic KRAS signalling not only instigates aberrant growth in cancer cells but can further inhibit anti-tumour immunity. Hence, recently developed KRAS G12C inhibitors (G12Ci) hold the potential to reshape the treatment landscape for eligible cancer patients. However, rewiring of oncogenic signalling circuits and acquisition of further mutations can lead to rapid development of drug resistance. Indeed, clinical trials for G12Ci Sotorasib in non-small-cell lung cancer revealed a median progression-free survival of only ~7 months, with no overall survival advantage compared to conventional chemotherapy.
In this project, we investigate strategies to combat the development of drug resistance to G12Ci, by fostering an anti-tumour immune response, capable of recognising a pan-cancer-cell archetype and thereby also eliminating drug-resistant cells. First, a preclinical murine model to mimic progression of drug resistance was established by co-engrafting reporter-traced, isogenic G12C and G12D-mutant lung cancer cells; the latter being inherently G12Ciincompatible. G12Ci alone can already alleviate mutant-KRAS-driven immune suppression and induce immunogenic cell death in G12Ci-responsive cells. Surprisingly, in our model, employing G12Ci as monotherapy drove therapy resistance by giving the drug-resistant subpopulation a proliferative advantage, which was further investigated through RNA-sequencing.
Next, combination therapies, further supporting immunity through synergy, were investigated. Combining G12Ci with immunotherapy or a SHP2 inhibitor potentiated an adaptive immune response, capable of eliminating both, G12C and G12D mutant cancer cells and further engendering immune-memory. Underlying mechanisms were investigated by immune-phenotyping of tumours across treatment groups, employing a 36-plex spectral flow cytometry panel. Additional spatial information was obtained through multiplex histopathology. This revealed profound TME remodelling in mice treated with combination therapies.
In this project, we investigate strategies to combat the development of drug resistance to G12Ci, by fostering an anti-tumour immune response, capable of recognising a pan-cancer-cell archetype and thereby also eliminating drug-resistant cells. First, a preclinical murine model to mimic progression of drug resistance was established by co-engrafting reporter-traced, isogenic G12C and G12D-mutant lung cancer cells; the latter being inherently G12Ciincompatible. G12Ci alone can already alleviate mutant-KRAS-driven immune suppression and induce immunogenic cell death in G12Ci-responsive cells. Surprisingly, in our model, employing G12Ci as monotherapy drove therapy resistance by giving the drug-resistant subpopulation a proliferative advantage, which was further investigated through RNA-sequencing.
Next, combination therapies, further supporting immunity through synergy, were investigated. Combining G12Ci with immunotherapy or a SHP2 inhibitor potentiated an adaptive immune response, capable of eliminating both, G12C and G12D mutant cancer cells and further engendering immune-memory. Underlying mechanisms were investigated by immune-phenotyping of tumours across treatment groups, employing a 36-plex spectral flow cytometry panel. Additional spatial information was obtained through multiplex histopathology. This revealed profound TME remodelling in mice treated with combination therapies.
Version
Open Access
Date Issued
2024-09-20
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Downward, Julian
Malanchi, Ilaria
Gil, Jesus
Sponsor
Francis Crick Institute
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)