Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations

Area of Science:

• Cancer Biology
• Epigenetics
• Metabolic Pathways

Background:

• Epigenetic alterations, particularly mutations in chromatin-modifying enzymes like COMPASS family members MLL3 and MLL4, are implicated in human diseases, including cancer.
• The functional consequences and resulting cellular dependencies of these mutations are not fully understood, hindering therapeutic development.

Purpose of the Study:

• To investigate cellular vulnerabilities arising from the loss of MLL3 and MLL4, focusing on compromised enhancer function.
• To identify potential therapeutic strategies targeting these dependencies in cancers with MLL3/4 mutations.

Main Methods:

• CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs).
• Metabolic activity assays, RNA-sequencing (RNA-Seq), and tandem mass tag (TMT) proteomic profiling.
• In vitro and in vivo drug sensitivity testing using the purine synthesis inhibitor lometrexol in cancer models.

Main Results:

• MLL3/4-depleted mESCs exhibited synthetic lethality with suppressed purine and pyrimidine nucleotide synthesis.
• A metabolic shift towards increased purine synthesis was observed in MLL3/4-deficient cells.
• MLL3/4-deficient cells showed enhanced sensitivity to lometrexol, with distinct gene expression changes.
• MLL1/COMPASS compensation was identified as a key mechanism.
• Tumors with MLL3 and/or MLL4 mutations demonstrated significant sensitivity to lometrexol.

Conclusions:

• Loss of MLL3/4 function leads to a targetable metabolic dependency on purine synthesis.
• Lometrexol represents a promising therapeutic agent for cancers harboring MLL3/4 mutations.
• Understanding epigenetic factor deficiency provides molecular insights for cancer therapy development.