The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models. Issue 3 (27th July 2022)

• Record Type: Journal Article
• Authors: Sigaud, Romain; Rösch, Lisa; Gatzweiler, Charlotte; Benzel, Julia; von Soosten, Laura; Peterziel, Heike; Selt, Florian; Najafi, Sara; Ayhan, Simay; Gerloff, Xenia F; Hofmann, Nina; Büdenbender, Isabel; Schmitt, Lukas; Foerster, Kathrin I; Burhenne, Jürgen; Haefeli, Walter E; Korshunov, Andrey; Sahm, Felix; van Tilburg, Cornelis M; Jones, David T W; Pfister, Stefan M; Knoerzer, Deborah; Kreider, Brent L; Sauter, Max; Pajtler, Kristian W; Zuckermann, Marc; Oehme, Ina; Witt, Olaf; Milde, Till
• Is Part Of: Neuro-oncology. Volume 25:Issue 3(2023)
• Page Start: 566
• Page End: 579
• Publication Date: 2022-07-27
• Subjects: BH3-mimetics -- ERK inhibitor -- MAPK inhibitor -- pediatric low-grade glioma -- synergism; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac183
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods: We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549 : BRAF -fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Results: Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. Conclusions: These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.