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Molidustat Targets a Synthetic Lethal Vulnerability in APC-Mutant Colorectal Cancer through GSTP1 and PHD2 Co-Inhibition

ABSTRACT: APC mutations drive colorectal cancer (CRC) and create dependencies on metabolic and stress-adaptation pathways. To investigate vulnerabilities associated with hydroxylase inhibition in APC-mutant cells, we profiled the proteomic consequences of the clinical PHD2 inhibitor Molidustat using thermal proteome profiling and chemical proteomics. These analyses revealed GSTP1 as an unexpected off-target interactor whose enzymatic activity is directly inhibited by Molidustat. Quantitative proteomics of CRISPR knockout models showed that loss of GSTP1 and PHD2 individually induces partially overlapping stress responses, whereas combined loss produces a synergistic redox-collapse phenotype, characterised by oxidative stress, apoptotic signalling, and impaired proliferation, closely recapitulating the cellular response to Molidustat. Metabolomics confirmed elevated oxidative pressure and altered redox balance in the double knockout. In parallel, Molidustat selectively reduced viability in APC- and KRAS-mutant colonic organoids, an effect not reproduced by other hydroxylase inhibitors. Together, these data identify a GSTP1–PHD2 synthetic lethal interaction and demonstrate that Molidustat exploits this vulnerability, providing a mechanistic basis for its selective activity in APC-mutant CRC.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Agata Makar

LAB HEAD: Alex von Kriegsheim

PROVIDER: PXD071906 | Pride | 2026-05-04

REPOSITORIES: Pride

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Project description:The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

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Dataset Information

Molidustat Targets a Synthetic Lethal Vulnerability in APC-Mutant Colorectal Cancer through GSTP1 and PHD2 Co-Inhibition

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