Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer

Area of Science:

• Oncology
• Metabolic pathways
• Cancer cell biology

Background:

• Therapy resistance and relapse in colorectal cancer (CRC) are linked to lipid droplet (LD) formation via de novo lipogenesis (DNL).
• The precise molecular mechanisms driving DNL and sensitivity to DNL-targeted therapies in CRC remain incompletely understood.
• Drug-tolerant persister cells (DTPs) in CRC exhibit increased DNL, contributing to therapeutic challenges.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying increased DNL in CRC DTPs.
• To investigate the role of Lipin1 (LPIN1) in LD formation and lipid homeostasis in CRC.
• To evaluate the therapeutic potential of targeting DNL and LD formation in CRC models.

Main Methods:

• Analysis of LPIN1 expression in CRC DTPs and its regulation via the ETS1-PTPN1-c-Src-CEBPβ pathway.
• In vitro studies using statins and LPIN1 inhibition to disrupt lipid homeostasis in DTPs and patient-derived organoids (PDOs).
• In vivo studies using CRC DTP mouse xenograft and patient-derived xenograft (PDX) models to assess therapeutic efficacy.

Main Results:

• CRC DTPs over-express LPIN1, facilitating free fatty acid sequestration into LDs.
• Blocking LD formation with statins or LPIN1 inhibition induces lipotoxicity and ferroptotic cell death in DTPs and PDOs.
• Ferroptosis inhibitors or N-acetylcysteine (NAC) rescue cells from LPIN1 inhibition-induced death, and this strategy reduces tumor growth in vivo.

Conclusions:

• LPIN1-mediated LD formation represents a metabolic vulnerability in CRC DTPs, PDOs, and PDX models.
• Targeting the conversion of phosphatidic acid (PA) to diacylglycerol (DAG) to prevent LD formation is a promising therapeutic strategy for therapy-resistant CRC.
• Repurposing statins offers a potential clinical approach to overcome therapy resistance in colorectal cancer.