Mechanism and Clinical Translation of BCL-2–Targeted Antitumor Therapy

Full abstract

Read the full abstract

The BCL-2 protein family plays a critical role in the process of apoptosis. By regulating the mitochondrial pathway, it directly influences cell survival and is of vital importance in tumorigenesis and tumor progression. Overly high level of anti-apoptotic proteins is expressed in tumor cells, including BCL-2, BCL-XL and MCL-1. Consequently, mitochondrial-mediated cell death is effectively blocked, allowing tumor cells to survive exposure to chemotherapy or targeted therapies. The reliance of cancer cells on BCL-2 proteins to sustain viability serves both as a key mechanism driving tumor progression and as an attractive focus for targeted therapeutic strategies. In recent years, a series of BH3 mimics and selective BCL-2 inhibitors, represented by Venetoclax, have been developed by scientists, and those drugs have been proved noticable effectiveness in providing treatment for tumors like Chronic Lymphocytic Leukemia (CLL), Acute Myeloid Leukemia (AML) and lymphoma. However, the degree of dependence on anti-apoptotic proteins varies significantly among different tumors, and resistance mechanisms are complex. Some tumors exhibit elevated level of BCL-XL or MCL-1 expression, while signaling pathways, such as PI3K/AKT/MAPK, enable others to survive, and still others involve the loss of function of BAX or BAD. This article summarizes the expression patterns and dependency characteristics of BCL-2 in common tumors and analyzes its role in carcinogenesis, treatment efficacy, and how drug resistance develops and eventually comes into form, with the aim of providing guidance for the clinical application of BH3 mimics and other targeted therapies.