Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality

Myeloid cell leukemia-1 protein (MCL-1) is a major anti-apoptotic member of the Bcl-2 family and is typically overexpressed in a broad range of malignancies, including non-small-cell lung cancer, multiple myeloma, acute myeloid leukemia, and various solid tumors. By sequestering pro-apoptotic effectors, MCL-1 maintains mitochondrial stability and supports the tumor cell survival during stress, driving disease progression, therapeutic resistance, and ultimately, poor patient outcomes. In the last 10 years, the development of selective small-molecule inhibitors of MCL-1 has opened doors to enable the targeting of this mechanism of apoptosis avoidance.

This perspective summarizes the current knowledge regarding the dual roles of MCL-1 in apoptosis and mitochondrial homeostasis regulation. The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The non-apoptotic roles of MCL-1 in immune modulation and metabolism adaptation are also reviewed, along with the development of analytical methods to refine the patient selection process (e.g., BH3 profiling and transcriptomic signatures). The overexpression of MCL-1 is associated with worse patient survival in ACC, CESC, ESCA, HNSC, LGG, and UVM cancers.

MCL-1 is an exciting anti-cancer target, and its inhibition may sensitize treatment-resistant tumors to cell death and enhance patient survival. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts.