Abstract Background Pediatric high-grade gliomas (pHGG) comprise a heterogenous group of tumors characterized by rapid growth and dismal survival. Taking advantage of molecular alterations is of utmost importance to increase overall survival for patients suffering from this devastating disease. BRAFV600E mutations occur in 5-15% and dabrafenib combined with mekinist was recently approved as targeted therapeutic intervention in this subgroup. Homozygous CDKN2A/B loss, a marker of aggressive glioma co-occurs in approximately 60%. Thus, we hypothesized that combined MEK and CDK4/6 inhibition improves anti-tumor effects in pHGG. Material and Methods Four BRAF-mutant pHGG tumor models with CDKN2A/B loss were preclinically tested for drug response, induction of senescence/apoptosis, and effects on cell cycle distribution with CDK4/6 inhibition alone or combined with trametinib upon short- and long-term exposure. Western blot and immunohistochemistry were applied to investigate effects on intracellular downstream signaling in cell models, human-to-organoid-transplants (HOT) and patient-derived xenografts (PDX). In a translational approach the combination was administered in one patient with progressive BRAF-altered anaplastic pleomorphic xanthoastrocytoma (aPXA). Results First, we compared effects of three different clinically applied CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib. As all investigated cell models showed highest sensitivity to abemaciclib, we further tested the combination with trametinib. Simultaneous induction of apoptosis and senescence was distinctly increased upon combination when compared to monotherapy. Regarding intracellular signaling, solely combined MEK and CDK4/6 inhibition suppressed PI3K/mTOR activation at the level of S6 in vitro and in vivo. HOT and PDX models showed increased survival and sustained therapy response even after treatment discontinuation. This approach was also shown to be clinically feasible in a therapy refractory aPXA for two years followed by stable disease for 30 months without treatment. Conclusion Summarizing, combined treatment with MEK and CDK4/6 inhibitors represents a promising treatment strategy in pHGG harboring simultaneous BRAF mutation and CDKN2A/B loss.
Mayr et al. (Fri,) studied this question.