Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited options for therapy. Cancer development and maintenance is dependent on the production of oncogenic proteins. In TNBC, the production of many of these proteins is changed, and therapeutic targeting of one of these proteins is often not effective. However, a common step in the production of these proteins, transcription, can be effectively targeted through inhibition of the transcriptional machinery. These inhibitors can specifically suppress the production of oncogenic proteins important for TNBC. At the same time, the altered production of these proteins might interfere with the sensitivity of these cancer cells to these inhibitors. This review provides an overview of the effects of inhibitors of the transcriptional machinery on the abnormal oncogenic protein production in TNBC. This overview thereby highlights the research further needed in this field, and the potential opportunities of using these inhibitors for TNBC. ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC.