Biology subjects

de Carne Trecesson, S.

Publications and source records attributed to de Carne Trecesson, S..

2 recordsLinked to original sources

bioRxiv2021

Oncogenic RAS activity predicts response to chemotherapy and outcome in lung adenocarcinoma

Activating mutations in the driver oncogene KRAS occur in 32% of lung adenocarcinomas, leading to more aggressive disease and resistance to therapy in preclinical studies. However, the association between KRAS mutational status and patient outcome or response to treatment remains unclear, likely due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation beyond KRAS mutation only, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in lung adenocarcinoma. Using RAS84 to classify lung cell lines, we show that RAS transcriptional activity outperforms KRAS mutation to predict resistance to chemotherapy drugs in vitro. We report that 84% of lung adenocarcinomas show clear transcriptional evidence of RAS oncogenic activation, falling into four groups characterised by coincident mutation of STK11/LKB1, TP53 or CDKN2A. Given that 65% of these RAS pathway active tumours do not have KRAS mutations, we find that the classifications developed when considering only KRAS mutant tumours have significance in a much broader cohort of patients. Critically, patients in the highest RAS activity groups show adverse clinical outcome and reduced response to chemotherapy. The stratification of patients using gene expression patterns linked to oncogenic RAS signalling activity instead of genetic alterations in cancer genes could ultimately help clinical decision making.

cancer biology↗

bioRxiv2020

APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumour mutational burden and autochthonous tumours remained refractory to immunotherapy. However, by establishing clonal cell lines from these tumours we generated an immunogenic syngeneic transplantation model of KRAS mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, we found that anti-tumour immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing versions of these tumours was markedly potentiated by the adaptive immune system, providing a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

cancer biology↗