Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma
- 1Institute of Cancer Research
Abstract
Diffuse midline glioma is an epigenetically driven disease defined by alterations targeting the histone post-translational modification H3K27me3 resulting in epigenetic rewiring and imposing unique metabolic dependencies. ACVR1-mutations arise in ~25% of DMG H3K27-altered patients and impart a selective dependency on the kinase it encodes (ALK2), however ALK2 inhibitors show modest single-agent efficacy in vivo. In an attempt to better understand the cellular consequences of ALK2 inhibition to identify mechanistically-driven drug combinations, integrated multi-omics analysis was performed and revealed a novel role for ALK2 in cholesterol homeostasis while CRISPR and high-throughput drug screens identified hits targeting cholesterol metabolism as sensitisers to ALK2i. In vivo assessment of ALK2i plus clinically well-tolerated statins revealed a significant increase in the median survival compared to vehicle. Forced differentiation of DMG cells from an oligodendrocyte precursor-like to an astrocyte-like cell-state and led to a significant decrease in ALK2i sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. We identify a previously unappreciated role for ALK2 signalling in cholesterol homeostasis, showing cell-state dependency, and identify a rational combinatorial strategy for clinical translation.
Related
- MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors
- FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers
- Lipid Metabolic Reprogramming in Thyroid Cancer: Systemic Biomarkers, Tumor Dependencies and Therapeutic Resistance
- 318 CAR-T and CAR-NK cell combination therapy targeting DLL3 or CD70 surface antigens promotes synergistic antitumor activity in small cell lung cancer
- Targeting cholesterol metabolism to overcome Zanubrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma
BibTeX
@misc{rogers2026combination,
title = {{Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma}},
author = {R. Rogers and Y. Grabovska and A. Mackay and D. Carvalho and C. Dobinson and R. Pereira and A. Burford and L. Bevington and V. Molinari and J. Song and H. Tari and R. Ruddle and J. Nkrumah and D. Sejdiu and N. Chew and V. Tsui and C. Sun and M. Vinci and G. Pericoli and O. Becher and J. Fortin and P. Sampson and R. Firestein and C. Jones},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753440},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma
AU - R. Rogers
AU - Y. Grabovska
AU - A. Mackay
AU - D. Carvalho
AU - C. Dobinson
AU - R. Pereira
AU - A. Burford
AU - L. Bevington
AU - V. Molinari
AU - J. Song
AU - H. Tari
AU - R. Ruddle
AU - J. Nkrumah
AU - D. Sejdiu
AU - N. Chew
AU - V. Tsui
AU - C. Sun
AU - M. Vinci
AU - G. Pericoli
AU - O. Becher
AU - J. Fortin
AU - P. Sampson
AU - R. Firestein
AU - C. Jones
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753440
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753440v1
AB - Diffuse midline glioma is an epigenetically driven disease defined by alterations targeting the histone post-translational modification H3K27me3 resulting in epigenetic rewiring and imposing unique metabolic dependencies. ACVR1-mutations arise in ~25% of DMG H3K27-altered patients and impart a selective dependency on the kinase it encodes (ALK2), however ALK2 inhibitors show modest single-agent efficacy in vivo. In an attempt to better understand the cellular consequences of ALK2 inhibition to identify mechanistically-driven drug combinations, integrated multi-omics analysis was performed and revealed a novel role for ALK2 in cholesterol homeostasis while CRISPR and high-throughput drug screens identified hits targeting cholesterol metabolism as sensitisers to ALK2i. In vivo assessment of ALK2i plus clinically well-tolerated statins revealed a significant increase in the median survival compared to vehicle. Forced differentiation of DMG cells from an oligodendrocyte precursor-like to an astrocyte-like cell-state and led to a significant decrease in ALK2i sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. We identify a previously unappreciated role for ALK2 signalling in cholesterol homeostasis, showing cell-state dependency, and identify a rational combinatorial strategy for clinical translation.
ER -