Rational Strategies for Combining Bcl-2 Inhibition with Targeted Drugs for Anti-Tumor Synergy

Based on the well-established importance of dysregulated apoptosis as a hallmark of cancer, there has been robust interest in development of targeted drugs to promote cancer cell apoptosis. A promising target for promoting apoptosis is the Bcl-2 family of proteins. Bcl-2 family proteins are crucial in maintaining balance between cell survival and death through regulation of apoptotic signaling pathways via pro-survival and pro-apoptotic family members. To date, there has been limited efficacy with Bcl-2 inhibition alone in clinical development with benefit restricted to hematologic malignancies. However, combination approaches to inhibition of Bcl-2 and other oncogenic signaling pathways have provided evidence for potential anti-tumor synergy. We review herein the current evidence for targeting Bcl-2 family proteins as a cancer therapeutic strategy across both hematologic and solid organ malignancies.