Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lin28 is a conserved protein implicated in cancer stem cell generation and poor patient prognosis.
• Lin28 binds and inhibits the maturation of the tumor suppressor microRNA (miRNA) let-7.
• Reduced let-7 levels promote cancer progression, including proliferation, invasion, metastasis, and drug resistance.

Purpose of the Study:

• To design and evaluate miRNA-based proteolysis-targeting chimeras (PROTACs) targeting Lin28A for degradation.
• To investigate the therapeutic potential of Lin28A degradation via PROTACs in preclinical cancer models.

Main Methods:

• Development of a series of Lin28A-miRNA-PROTACs designed to induce ubiquitin-proteasome-dependent degradation of Lin28A.
• Assessment of PROTAC efficacy in restoring mature let-7 miRNA levels.
• Evaluation of the impact of Lin28A degradation on cancer cell proliferation, migration, and chemotherapy sensitivity.
• In vivo testing of Lin28A-miRNA-PROTACs in a mouse ectopic tumor model, including combination therapy with tamoxifen.

Main Results:

• The developed Lin28A-miRNA-PROTACs efficiently degrade Lin28A via a ubiquitin-proteasome pathway.
• Degradation of Lin28A led to significant up-regulation of mature let-7 miRNAs.
• Restored let-7 levels inhibited cancer cell proliferation and migration and enhanced chemotherapy sensitivity.
• Lin28A-miRNA-PROTACs demonstrated substantial tumor growth inhibition in vivo, with notable regression when combined with tamoxifen.

Conclusions:

• miRNA-based PROTACs represent an effective strategy for targeted degradation of Lin28A.
• This approach restores tumor suppressor miRNA let-7 activity, leading to inhibition of cancer progression.
• Lin28A-miRNA-PROTACs show significant therapeutic promise for cancer treatment, particularly in combination therapies.