Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.

Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, McKernan C, Sanchez V, Balko JM, Stricker T, Estrada MV, Cook RS
Mol Cancer Res. 2017 15 (3): 259-268

PMID: 28039357 · PMCID: PMC5334148 · DOI:10.1158/1541-7786.MCR-16-0280-T

An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of as compared with or (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured using Mcl-1/Bim proximity ligation assays. Importantly, gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of or and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing. Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. .

©2016 American Association for Cancer Research.

MeSH Terms (15)

Aniline Compounds Antineoplastic Agents bcl-X Protein Breast Neoplasms Cell Line, Tumor Cell Survival Estrogen Receptor alpha Female Humans MCF-7 Cells Myeloid Cell Leukemia Sequence 1 Protein Neoplasms Proto-Oncogene Proteins c-bcl-2 RNA, Messenger Sulfonamides

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