Dual Targeting of Nucleotidase-Dependent and -Independent Functions via PROTAC-Mediated CD73 Degradation

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• CD73 (ecto-5'-nucleotidase) promotes tumor progression and immunosuppression via enzymatic and nonenzymatic pathways.
• Current CD73-targeted therapies (inhibitors, antibodies) have limited efficacy.
• Novel strategies are needed to overcome CD73-mediated tumor defense mechanisms.

Purpose of the Study:

• To develop and characterize a first-in-class proteolysis-targeting chimera (PROTAC) for CD73 degradation.
• To evaluate the efficacy of the PROTAC C79 in preclinical cancer models.
• To elucidate the mechanisms underlying C79's anti-tumor effects.

Main Methods:

• Development of NUCC-0227579 (C79), a VHL E3 ligase-dependent PROTAC targeting CD73.
• Assessment of C79's ability to degrade CD73 in cancer cell lines and humanized mouse models.
• Analysis of C79's impact on immune cell signaling, tumor cell functions, and tumor growth.

Main Results:

• C79 effectively degraded CD73 in cancer cells, abolishing enzymatic activity and reversing immunosuppression.
• C79 enhanced T cell activation and cytokine production (IFN-γ, TNF-α).
• C79 impaired tumor cell proliferation, migration, and adhesion via non-nucleotidase-dependent mechanisms.
• C79 suppressed tumor growth and enhanced antitumor immunity in triple-negative breast cancer models.

Conclusions:

• CD73 degradation via PROTACs represents a mechanistically distinct strategy against cancer.
• C79 demonstrates superior efficacy compared to enzymatic inhibitors in preclinical models.
• Targeting CD73 for degradation offers a promising therapeutic avenue to overcome current treatment limitations.