Targeting PRMT1 Reduces Cancer Persistence and Tumor Relapse in EGFR- and KRAS-Mutant Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Incomplete eradication of cancer cells during treatment leads to disease relapse.
• Targeting oncogenic drivers like EGFR and KRASG12C is a key strategy in lung cancer therapy.
• Cancer cell persistence poses a significant challenge to achieving durable treatment responses.

Purpose of the Study:

• To identify molecular mechanisms enabling cancer cell persistence during oncogene-targeted therapy.
• To investigate the role of type I protein arginine methyltransferases (PRMTs) in cancer cell persistence.
• To evaluate PRMT1 as a therapeutic target for overcoming resistance in EGFR- or KRASG12C-mutant lung cancer.

Main Methods:

• Utilized cell line and xenograft models of EGFR- and KRASG12C-mutant lung cancer.
• Performed knockdown experiments for PRMT1, PRMT4, and PRMT6 isoforms.
• Administered PRMT1 inhibitors in combination with EGFR or KRASG12C inhibitors.
• Assessed cancer cell persistence, regrowth, and tumor regression.

Main Results:

• PRMT1 knockdown, combined with targeted inhibitors, reduced cancer cell persistence and delayed regrowth.
• Knockdown of PRMT4 and PRMT6 isoforms increased cancer cell persistence.
• Targeting PRMT1 showed greater efficacy in lung cancer models with an intact chromosome 5q31.1 region.

Conclusions:

• PRMT1 is a critical factor enabling cancer cell persistence in EGFR- or KRASG12C-targeted therapies.
• Targeting PRMT1 offers a novel strategy to eliminate persister cells and improve treatment outcomes.
• The status of chromosome 5q31.1 may serve as a predictive biomarker for PRMT1-targeted therapy efficacy.