Effects of Combination Therapy of a CDK4/6 and MEK Inhibitor in Diffuse Midline Glioma Preclinical Models
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Diffuse midline glioma (DMG) is an incurable brain cancer without a single FDA-approved drug that prolongs survival. CDK4/6 inhibitors have been evaluated in children with DMG with limited efficacy. Since MAPK pathway activation is upstream of cell proliferation, we hypothesized that MEK inhibitors may increase the anti-tumor effects of CDK4/6 inhibitors. Here, we evaluated the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in human and murine DMG models to investigate combinational effects.
Methods
We conducted in vitro and in vivo assays using DMG cell lines from human patient-derived xenografts (PDX) and murine genetically engineered models (GEM). In vitro, we assessed synergy across human DMG lines. In vivo , we evaluated therapeutic effects with histological examinations, survival analysis, pharmacokinetic measurements, and RNA-sequencing analysis.
Results
In vitro , ribociclib and trametinib had variable synergistic effects against human DMG cell lines. In vivo , a five-day treatment with combination therapy in the GEM DMG model significantly decreased cell proliferation and increased apoptosis compared with the vehicle, with trametinib having mostly cytotoxic effects and ribociclib having primarily cytostatic effects. In addition, a 21-day treatment with combination therapy significantly prolonged mice survival compared with the vehicle in the GEM DMG model (median survival: 112 days vs. 71.5 days, log rank test p=0.0195). In an orthotopic PDX model, combination therapy did not prolong mice survival compared with vehicle, ribociclib, and trametinib. LC/MS analysis showed adequate drug delivery across the blood-brain-barrier (BBB) into tumor tissue in both GEM and PDX models. Transcriptomic analysis in the GEM model suggests that combination therapy inhibited the MAPK pathway and inflammation.
Conclusions
Combination therapy with ribociclib and trametinib significantly prolonged survival in the GEM model but not in the PDX model, highlighting the importance of testing novel therapies in diverse models.
Key Points
Combination therapy had cytotoxic and cytostatic effects in vivo in the GEM model.
Combination therapy had variable synergy in vitro in human DIPG models.
Combination therapy significantly prolonged mice survival compared with the vehicle in the GEM model.
Combination therapy did not prolong survival in the PDX model.
Transcriptional analysis suggests that the combination modulated inflammation in the GEM model.
This work highlights the importance of testing novel therapies in diverse models.
Importance of the Study
DMG is an incurable brain cancer without a single FDA-approved drug that prolongs survival. CDK4/6 inhibitors have been evaluated in children with DMG with limited efficacy. As MAPK pathway activation is known to be upstream of cell proliferation, we hypothesize that combination therapy will have additive effects relative to monotherapy. In this study, we evaluated the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in GEM and PDX DMG models. In vitro , the inhibitor combination demonstrated variable synergy in DMG human cell-lines, but in vivo , it had limited efficacy in a PDX orthotopic model. In the GEM model, the combination prolonged survival compared with the vehicle and with single agents. PK studies showed similar drug levels in tumor tissue between the GEM and PDX models. Transcriptomic analysis in the GEM suggests that the drug combination significantly inhibited inflammation. These results highlight the importance of testing therapies in diverse models and suggest that this combination may be an effective therapy in patients with DMG.
