PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer

Abstract

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.

AZD1208, a pan‐Pim kinase inhibitor, inhibits adipogenesis and induces lipolysis in 3T3‐L1 adipocytes

“…AZD1208 is a thiazolidine that is highly selective for all Pim isoforms and is known for its anti‐cancer activity . As of now, neither the anti‐obesity effect nor the mode of action of AZD1208 in adipocytes is reported.…”

Androgen deprivation therapy has no effect on Pim-1 expression in a mouse model of prostate cancer

“…To date, three members of oncogenic serine/threonine kinases genes, including the highly homologous Pim-1, Pim-2 and Pim-3, have been reported in the PIM family, and possess overlapping structures and functions. Among them, Pim-1 has been widely investigated and its oncogenic nature has been confirmed (14). The crystal structure reveals that Pim-1 is a constitutively active kinase.…”

“…Pim kinases may be associated with the regulation of gene transcription through interactions with c-Myc and AKT to enhance tumorigenesis and inactivate cell cycle inhibitors by phosphorylating and downregulating p27Kip1 at the transcriptional and post-transcriptional levels (23,24). Furthermore, Pim may be involved in the regulation of cell proliferation and viability (14).…”

Molecular-Genetic «portrait» of Breast Cancer

“…В частности, показано, что использование инги-битора ПК PIM1, активация которой характерна для «трижды негативного» молекулярного подтипа карцином молочной железы, замедляет пролифе-рацию опухолевых клеток в клеточных культурах РМЖ [35]. Применение ингибитора лиганда про-гестеронрегулируемого рецептора RANK (Дено-сумаб) в рамках пилотного клинического иссле-дования продемонстрировало снижение проли-ферации клеток молочной железы у носительниц мутаций в гене BRCA1 [36,37].…”