Scientific Programmes

Molecular Oncology Programme

Experimental Oncology Group

Group Leader:  Mariano Barbacid
Overview

KRAS oncogenes have been implicated in about one fifth of all human cancers including lung and pancreatic adenocarcinomas, 2 of the tumour types with the worst prognosis. Unfortunately, identification of suitable therapies to treat these tumours remains elusive and patients are still treated with cytotoxic compounds approved over 2 decades ago. The recent discovery that these tumours display intra-tumour heterogeneity adds another layer of complexity that needs to be addressed. Hence, our laboratory has decided to search for novel therapeutic targets that may contribute to the early stages of lung tumour development, hoping that these targets will be present in all tumour cells – including cancer initiating cells and cancer stem cells – and not only in limited populations of evolving clones. In addition, we have continued our quest to validate known targets (mainly those of the MAPK and PI3K pathways) using genetically engineered mouse tumour models with the ultimate goal of establishing rational combination therapies that may provide significant therapeutic benefits in the clinic.

Significance
  • We have shown that human lung tumours respond efficiently to combinations of DDR1 and NOTCH inhibitors in PDX models.
  • We have provided a mechanistic explanation for the exclusive presence of K-RAS or EGFR mutations in human lung adenocarcinomas.
  • We have demonstrated that the different incidence of H-RAS and K-RAS oncogenes in human tumours is due to the signalling intensity of their respective oncoproteins.