Engineering aptamer-directed phosphatase recruiting chimeras: a strategy for modulating receptor function and...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Receptor tyrosine kinases (RTKs) are crucial in cell signaling and cancer development.
• Current kinase inhibitors face challenges with off-target effects and drug resistance.
• Novel strategies are needed to modulate RTK function effectively.

Purpose of the Study:

• To develop a novel approach, Aptamer-directed Phosphatase Recruiting Chimeras (Apt-PRCs), for attenuating cell-surface receptor signaling.
• To demonstrate the efficacy of Apt-PRCs in dephosphorylating specific RTKs like EGFR and MET.
• To evaluate the potential of Apt-PRCs in overcoming drug resistance in cancer.

Main Methods:

• Design and construction of Apt-PRCs, comprising an aptamer for phosphatase recruitment and a binder for receptor targeting.
• In vitro and in vivo experiments to assess the dephosphorylation activity and signaling inhibition by Apt-PRCs.
• Evaluation of Apt-PRC efficacy in enhancing sensitivity to gefitinib in drug-resistant cancer models.

Main Results:

• Apt-PRCs successfully achieved direct dephosphorylation of target RTKs (EGFR, MET).
• Apt-PRCs demonstrated specific and efficient inhibition of phosphorylation signal reception and transmission.
• Induced dephosphorylation by Apt-PRCs enhanced gefitinib sensitivity in resistant cancer cells and a mouse model.

Conclusions:

• Apt-PRCs represent a versatile methodology for modulating receptor phosphorylation and downstream signaling.
• This approach shows significant potential for overcoming drug resistance in cancer therapy.
• Apt-PRCs offer a promising alternative strategy for targeting RTK signaling pathways.