Abstract
MCL1 is an anti-apoptotic member of the BCL2 protein family, and its overexpression is associated with poor prognosis across various cancers. Small molecule inhibitors targeting MCL1 are currently in clinical trials for TNBC and other malignancies. However, one major challenge in the clinical application of MCL1 inhibitors is the inherent or acquired resistance to these drugs. Additionally, there is a lack of predictive biomarkers to identify which tumors will respond to MCL1 inhibition. We identified a four-gene functional signature that promotes MCL1 inhibitor resistance in TNBC cells. This gene signature (GS) can distinguish resistant from sensitive TNBC cell lines. Factors encoded by these four genes promote MCL1 inhibitor resistance at least in part through regulation of the ERK signaling pathway. This mechanism involves the upregulation of BCL2 and the downregulation of BIM, which contribute to the inhibitor resistance. Thus, we have discovered a functional GS that drives MCL1 inhibitor resistance. Currently, the MCL1 inhibitor GS-9716 is in clinical trials for TNBC therapy. If validated in clinical samples, this GS could potentially serve as a predictive biomarker for therapy response and help guide the selection of combination therapies to enhance the effectiveness of MCL1 inhibitors.