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  3. Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition

Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition

  • Neoplasia. 2025 Oct 27:70:101243. doi: 10.1016/j.neo.2025.101243.
Rachele Niccolai 1,  Camiel Göbel 1,  Klevis Ndoj 2,  Maaike Kreft 1,  Hendrik J Kuiken 3,  Cor Lieftink 3,  Ben Morris 3,  Sietse D Yska 1,  Sebastian Hendrix 2,  Bram van den Broek 4,  Vincent Pappalardo 5,  Marie José Kersten 6,  Roderick L Beijersbergen 3,  Noam Zelcer 2,  Fred van Leeuwen 7,  Heinz Jacobs 8
Affiliations

Affiliations

  • 1 Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 2 Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences Institute, The Netherlands; Amsterdam Gastroenterology, Metabolism and Endocrinology Institute, The Netherlands.
  • 3 Division of Molecular Carcinogenesis, Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 4 Department of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands; BioImaging Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 5 Biostatistics Center, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 6 Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
  • 7 Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Biology, Amsterdam UMC, University of Amsterdam, The Netherlands. Electronic address: fred.v.leeuwen@nki.nl.
  • 8 Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands. Electronic address: h.jacobs@nki.nl.
PMID: 41151153 DOI: 10.1016/j.neo.2025.101243
Abstract

The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 Inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the Cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous Cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated Cholesterol biosynthesis as a compensatory response, rendering cells sensitive to Cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of Cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the Cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved Cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.

Keywords

CRISPR-Cas9 screen; Cholesterol Biosynthesis; Diffuse large B cell lymphoma; EZH2; LDL-receptor.

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