Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• KRAS mutations are common in cancer, and KRAS inhibitors show promise.
• Resistance to KRAS inhibitors is a significant clinical challenge.
• Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is implicated in drug resistance.

Purpose of the Study:

• To investigate the role of ALDH1A1 in resistance to KRAS inhibitors.
• To explore mechanisms by which ALDH1A1 confers resistance.
• To evaluate therapeutic strategies targeting ALDH1A1.

Main Methods:

• Studied ALDH1A1 expression in response to KRAS inhibitors in cancer cells, patient-derived organoids, and xenograft models.
• Utilized ALDH1A1 knockout and functional inhibition.
• Investigated the interplay between ALDH1A1, ferroptosis, and the CREB1/GPX4 pathway.
• Examined the role of GTF2I phosphorylation in ALDH1A1 upregulation.

Main Results:

• ALDH1A1 expression increases upon KRAS inhibitor treatment, conferring resistance.
• ALDH1A1 knockout or inhibition significantly enhances KRAS inhibitor efficacy.
• ALDH1A1 counteracts ferroptosis by detoxifying aldehydes, boosting NADH/retinoic acid synthesis, and activating the CREB1/GPX4 pathway.
• KRAS inhibitors induce GTF2I dephosphorylation, leading to ALDH1A1 upregulation.

Conclusions:

• ALDH1A1 is a key mediator of resistance to KRAS inhibitors across various cancer models.
• Targeting ALDH1A1 can re-sensitize tumors to KRAS-targeted therapy.
• Enhancing ferroptosis by inhibiting ALDH1A1 represents a promising strategy for overcoming KRAS inhibitor resistance.