Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• c-Myc (Myc) oncogene drives aggressive cancer phenotypes and resistance to therapy.
• Identifying novel therapeutic targets in Myc-driven cancers is crucial for improving patient outcomes.

Purpose of the Study:

• To identify and characterize novel therapeutic targets in Myc-driven cancers.
• To elucidate the mechanisms by which dihydroorotate dehydrogenase (DHODH) contributes to Myc-driven tumorigenesis.
• To evaluate the therapeutic potential of targeting DHODH in Myc-driven cancers.

Main Methods:

• CRISPR-Cas9 screening was employed to identify potential therapeutic targets.
• Co-immunoprecipitation and Western blotting were used to investigate protein interactions and stability.
• Quantitative PCR and metabolic assays assessed gene expression and metabolic pathway activity.
• In vivo antitumor efficacy studies were conducted using drug combinations.

Main Results:

• Dihydroorotate dehydrogenase (DHODH) was identified as a key target in Myc-driven cancers.
• DHODH stabilizes Myc independently of its enzymatic activity by inhibiting SKP2-mediated degradation.
• Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense.
• Combining a DHODH inhibitor with a Myc inhibitor (EN4) showed significant antitumor activity in preclinical models.

Conclusions:

• DHODH plays dual roles in Myc-driven cancers, acting both metabolically and non-metabolically.
• The DHODH-Myc axis is a critical driver of colorectal cancer progression and is associated with poor prognosis.
• Targeting both the enzymatic and non-enzymatic functions of DHODH presents a promising therapeutic strategy for Myc-driven cancers.