Folate trapping is lethal to cancer cells.

Area of Science:

• Biochemistry
• Metabolic pathways in cancer
• Enzyme inhibition

Background:

• Mitochondrial MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) role in cancer cell formate metabolism is unclear.
• Previous studies explored inhibitors of cytosolic and nuclear MTHFD1/MTHFD2, with limited success.
• Mitochondrial MTHFD2's specific function in folate metabolism requires further investigation.

Purpose of the Study:

• To investigate the role of mitochondrial MTHFD2 in cancer cell survival and its potential as a therapeutic target.
• To elucidate the mechanism of "folate trapping" toxicity induced by MTHFD2 inhibition.
• To evaluate the efficacy of targeting MTHFD2 in various cancer types.

Main Methods:

• Utilized a potent inhibitor (TH9619) targeting dehydrogenase and cyclohydrolase activities.
• Investigated the impact of the inhibitor on formate flux and folate metabolism.
• Assessed cancer cell kill in cell lines expressing mitochondrial MTHFD2.

Main Results:

• Inhibition of mitochondrial MTHFD2 (mTHFD2) by TH9619 leads to "folate trapping" toxicity.
• mTHFD2 is essential for formate flow to the cytosol, crucial for this toxicity.
• Cancer cells expressing mTHFD2 are susceptible to TH9619-induced cell death.

Conclusions:

• Targeting mitochondrial MTHFD2 represents a promising therapeutic strategy for cancers overexpressing this enzyme.
• The "folate trapping" mechanism offers a novel approach for cancer treatment.
• Further evaluation in breast, prostate, colorectal, and AML is warranted.