Tumor-selective Mcl1 degradation by AUTAC uncouples antitumor efficacy from cardiotoxicity

Area of Science:

• Molecular Biology
• Oncology
• Pharmacology

Background:

• Mcl1 is crucial for therapeutic resistance in hematologic malignancies.
• Direct Mcl1 inhibition is limited by cardiotoxicity.

Purpose of the Study:

• To evaluate the efficacy and safety of Mcl1-targeting autophagy-targeting chimeras (AUTACs).
• To determine if AUTAC-mediated Mcl1 degradation offers a tumor-selective therapeutic window that spares cardiac tissue.

Main Methods:

• Development of an Mcl1-targeting AUTAC.
• Assessment of AUTAC-induced cytotoxicity and Mcl1 degradation in multiple myeloma models.
• Evaluation of AUTAC toxicity in cardiac cell lines, primary cardiomyocytes, and murine heart tissue.
• In vivo studies to assess tumor-selective Mcl1 reduction and cardiac Mcl1 levels.
• Mechanistic studies investigating factors contributing to selectivity.

Main Results:

• AUTAC induced potent cytotoxicity and Mcl1 degradation in multiple myeloma models.
• AUTAC demonstrated minimal toxicity in cardiac cells and tissues.
• In vivo, AUTAC reduced tumor Mcl1 without affecting cardiac Mcl1.
• Selectivity was linked to lower expression of key AUTAC machinery and reduced intracellular accumulation in cardiac cells.
• AUTAC enhanced the activity of carfilzomib and venetoclax without increasing cardiotoxicity.

Conclusions:

• AUTAC-mediated Mcl1 degradation provides a cardiac-sparing strategy for targeting Mcl1.
• Tumor-selective lysosomal degradation represents a safer therapeutic approach for Mcl1-directed therapy.
• AUTAC offers a promising alternative to classical Mcl1 inhibitors with reduced cardiotoxicity.