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PRSS contributes to cetuximab resistance in colorectal cancer
Zhaoli Tan1,2, Lihua Gao1, Yan Wang2
1Beijing Institute of Biotechnology, 20 Dongdajie, Beijing, China.
Abstract:
Cetuximab improves the survival of patients with metastatic colorectal cancer. The main limitation is primary and secondary resistance, the underlying mechanism of which requires extensive investigation. We proved that PRSS expression levels are significantly negatively associated with the sensitivity of cancer cells to cetuximab. Detailed mechanistic analysis indicated that PRSS can cleave cetuximab, leading to resistance. Cetuximab or bevacizumab combined with SPINK1, a PRSS inhibitor, inhibited cell growth more efficiently than cetuximab or bevacizumab alone in xenograft models. PRSS levels in the serum of 156 patients with mCRC were analyzed, and poor efficacy of cetuximab therapy was observed in patients with aberrant PRSS expression. PRSS expression in monoclonal antibody (mAb)-treated patients with cancer from The Cancer Genome Atlas database was also evaluated to determine whether patients with higher PRSS expression have significantly reduced progression-free survival. Our work provides a strong scientific rationale for targeting PRSS in combination with cetuximab therapy.
Insights
Protease serine (PRSS) cleaves cetuximab, causing resistance in metastatic colorectal cancer. Inhibiting PRSS with SPINK1 alongside cetuximab improves treatment efficacy and patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cetuximab is a monoclonal antibody (mAb) that improves survival in metastatic colorectal cancer (mCRC).
- Primary and secondary resistance to cetuximab significantly limits its clinical efficacy.
- The mechanisms underlying cetuximab resistance require further investigation.
Purpose of the Study:
- To investigate the role of Protease Serine (PRSS) in cetuximab resistance in mCRC.
- To elucidate the mechanism by which PRSS contributes to cetuximab resistance.
- To evaluate the therapeutic potential of targeting PRSS in combination with cetuximab or bevacizumab.
Main Methods:
- Assessed the association between PRSS expression levels and cetuximab sensitivity in cancer cells.
- Performed mechanistic analysis to determine if PRSS cleaves cetuximab.
- Evaluated the efficacy of combined cetuximab/bevacizumab with a PRSS inhibitor (SPINK1) in xenograft models.
- Analyzed PRSS serum levels in 156 mCRC patients and correlated with cetuximab efficacy.
- Examined PRSS expression in The Cancer Genome Atlas (TCGA) database for patients treated with monoclonal antibodies (mAbs).
Main Results:
- PRSS expression levels were significantly negatively associated with cetuximab sensitivity.
- PRSS was shown to cleave cetuximab, directly causing resistance.
- Combination therapy (cetuximab/bevacizumab + SPINK1) demonstrated superior inhibition of tumor growth compared to monotherapy in xenograft models.
- Aberrant PRSS expression in mCRC patients correlated with poor cetuximab efficacy.
- Higher PRSS expression was associated with significantly reduced progression-free survival in mAb-treated cancer patients from TCGA.
Conclusions:
- PRSS is a key mediator of cetuximab resistance in mCRC by cleaving the antibody.
- Targeting PRSS, particularly in combination with SPINK1, represents a promising strategy to overcome cetuximab resistance.
- PRSS expression serves as a predictive biomarker for cetuximab therapy response in mCRC.
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