Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Interrogation of genomic datasets identified increased PIM1 copy number-driven expression in TNBC. RNA interference in breast cancer and non-malignant mammary epithelial cell models revealed a PIM1 dependency in TNBC cells for proliferation and apoptotic protection, absent in non-malignant cells. PIM1 knockdown reduced BCL2 expression, and dynamic BH3 profiling analysis revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. PIM1 expression associates with several MYC-transcriptional signatures and promotes cell population growth through regulation of c-MYC and transcription of MYC-targets, including MCL1. The pan-PIM kinase inhibitor AZD1208 inhibited growth and sensitized TNBC cell lines, xenografts and patient-derived xenografts to standard of care chemotherapy. We identify PIM1 as a malignant cell-selective target in TNBC, illustrating relationships with MYC activation, regulation of anti-apoptotic BCL2 and MCL1, established TNBC oncogenic proteins SHP2 and EPHA2 and cell cycle inhibitor p27. Finally we identify a potential use of PIM1 inhibitors to abrogate TNBC's high threshold to TNBC standard of care chemotherapy induced apoptotic cell death.

Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification.