Role of the Notch pathway in lung adenocarcinoma : beyond the KrasG12V mouse model

Orateur : Antonio MARAVER (IRCM, Montpellier)

Lung cancer claims nearly a million deaths every year worldwide, and it is estimated that over 250 million people will die from this devastating disease during the 21st century. Identifying new pathways involved in the biological processes necessary for the survival of lung cancerous cells is paramount for developing new clinical approaches to prevent disease recurrence. Importantly, we have demonstrated using genetically engineered mouse models (GEMMs), that KrasG12V-driven lung adenocarcinomas (LUADs) are addicted to the Notch pathway, and that pharmacological inhibition of this pathway arrests autochthonous KrasG12V-driven LUAD tumour growth in vivo. To properly establish Notch inhibitors as a potential treatment for LUAD in patients, we urgently need to define the percentage and type of patients that could benefit from this treatment and we also need to prove that Notch inhibition have an impact in the clinically relevant model of patient derived xenografts (PDXs). Indeed, it is possible that Notch might be also activated in LUADs harbouring different oncogenic insults. If this were the case, Notch-targeting therapies could be beneficial to many more patients. To assess the relevance of using Notch inhibitors in a broader range of patient subtypes, we are using now LUAD GEMMs harbouring oncogenic EGFR mutation and EML4-ALK translocation. We are also analysing the putative beneficial effect of inhibiting the Notch pathway in combination with the targeted therapies for EGFR or ALK used today in the clinic. Finally, we are also testing chemical Notch inhibition in a new collection of LUAD PDXs with a range of different oncogenic mutations.

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