Seminar

The multifaceted roles of RAS-PI3K signalling in KRAS-driven lung tumour progression

Esther Castellano Sanchez, PhD

Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer. The prognosis is poor with a 15% overall 5?year survival rate for patients with advanced disease. This is attributable to the presence of metastasis at the time of diagnosis. KRAS mutations occur in approximately 25% of NSCLC patients. Unfortunately, understanding oncogenic changes in NSCLC has not provided effective long-term therapeutic strategies. Thus, there is a profound need to uncover the molecular mechanisms of RAS-driven lung tumours to develop new therapies to target NSCLCs. We have shown in a mouse model of lung cancer that disruption of RAS signalling through PI3-Kinase (PI3K), one of its main effectors, is essential for RAS driven tumour initiation and maintenance. We have shown that genetically blocking the interaction of RAS with p110? causes partial regression of established tumours, followed by long-term tumour stasis, although by itself it is not sufficient to cause complete regression in the autochthonous setting. Interestingly, simultaneous inhibition of p110? together with inhibition of ERK, another major RAS effector pathway, causes major tumour regression1. Proteomic analysis of regressing lung tumours lacking RAS-PI3K signalling showed significant changes in proteins involved in the function of cancer associated fibroblasts, where RAS-PI3K controlled proteins involved in cell adhesion and actin cytoskeleton reorganization, especially contractility. This correlated with a decrease in cell migration via regulation of Reelin (Reln) expression in fibroblasts. Our data shows that RAS-PI3K regulation of Reln is essential for proper cell migration and failure of regulation of this pathway results in loss of Reln expression and increased migratory phenotype both in in vitro and in vivo settings. Ways to re-express Reelin in tumours in lung tumours lacking Reln expression might be explored as a therapeutic approach to reduce cancer cell migration and to improve patient outcome2.