Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers
Menée in vitro et in vivo, cette étude met en évidence des mécanismes associés à l'activité antitumorale d'une inhibition combinée de mTORC1 et MEK pour le traitement d'une tumeur du système nerveux présentant un gène NF1 muté
NF1 encodes a RAS GTPase-Activating Protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1/MEK inhibition in vivo. We unexpectedly found that the glucose transporter, GLUT1, was potently suppressed but only when both pathways were inhibited. Moreover, unlike VHL and LKB1 mutant cancers, reduction of 18F-FDG uptake required the suppression of both mTORC1 and MEK. Together these studies identify optimal and sub-optimal therapeutic targets in NF1-mutant malignancies and define a non-invasive means of measuring combined mTORC1/MEK inhibition in vivo, which can be readily incorporated into clinical trials.