Defining Key Signaling Nodes and Therapeutic Biomarkers in NF1-Mutant Cancers

Abstract

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.

Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

“…2). Similar results were recently found in NF1 mutant tumors; however, here a combination of targeted agents (e.g., mitogen-activated protein kinase and mammalian target of rapamycin [mTOR] inhibition) was required for robust inhibition of 18 F-FDG consumption (20). Attenuated 18 F-FDG consumption was observed within hours of the combination treatment and could predict therapeutic outcome.…”

“…Consequently, acute inhibition of these signaling cascades with molecularly targeted therapies can attenuate glucose metabolism and disrupt the metabolic homeostasis of the tumor (14,15,19). Importantly, data suggest that decreased glucose metabolism contributes to the therapeutic response to targeted agents (20). As such, sustained oncogenic signaling in the presence of a drug, which can be a consequence of pharmacodynamic failure or drug resistance (intrinsic or adaptive), can be associated with persistent tumor glycolytic activity (15).…”

Sexual dimorphism in glioma glycolysis underlies sex differences in survival

“…Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the resultant production of 2-hydroxyglutarate (2-HG) can potentially inhibit glucose metabolism (28)(29)(30). Mutations in the neurofibromin 1 (NF1) tumor suppressor may have the ability to regulate glucose metabolism, at least in part through enhanced Akt/mTOR activity and increased expression of glucose transporters (31)(32)(33). The effects of mutations in the Capicua transcriptional repressor (CIC) gene on glucose metabolism are not well characterized; however, CIC mutations can cooperatively regulate 2-HG levels with IDH1 mutations in cell lines (34).…”

Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers

“…While effects are only cytostatic, mTORC1 inhibitors are surprisingly more potent than MEK inhibitors, underscoring the importance of this pathway in this tumor type (11). Moreover, when combined with MEK inhibitors, mTORC1 inhibitors trigger cell death and dramatic tumor regression in vivo (11).…”

“…While effects are only cytostatic, mTORC1 inhibitors are surprisingly more potent than MEK inhibitors, underscoring the importance of this pathway in this tumor type (11). Moreover, when combined with MEK inhibitors, mTORC1 inhibitors trigger cell death and dramatic tumor regression in vivo (11). Nevertheless, because these 2 major pathways regulate so many fundamental biological processes, it may be challenging to identify an effective therapeutic window in humans using combined MEK/ mTORC1 inhibitors.…”