An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Targeting oncogenic RAS proteins has been a significant challenge in cancer therapy for decades.
• Small-molecule inhibitors have faced limitations in achieving broad RAS inhibition.

Purpose of the Study:

• To develop a novel biologic inhibitor for broad targeting of oncogenic RAS proteins.
• To evaluate the efficacy of this inhibitor in preclinical cancer models.

Main Methods:

• Engineered a chimeric toxin by fusing a RAS-RAP1-specific endopeptidase with diphtheria toxin's protein delivery system.
• Assessed the inhibitor's ability to cleave and inactivate intracellular RAS in vitro.
• Evaluated in vivo target engagement and tumor burden reduction in mouse xenograft models with wild-type or mutant RAS.

Main Results:

• The engineered chimeric toxin irreversibly cleaved and inactivated intracellular RAS at low picomolar concentrations.
• Downstream signaling was terminated in receptor-bearing cells.
• Demonstrated in vivo target engagement and significant reduction in tumor burden across three different RAS-driven xenograft models.

Conclusions:

• Intracellular delivery of a potent anti-RAS biologic via a receptor-mediated mechanism is a viable strategy.
• This approach offers a promising therapeutic avenue for a broad spectrum of RAS-driven cancers.