PIM kinases have already been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future. Subject terms: Molecular medicine, Germ cell tumours Introduction Prostate cancer (PCa) is one of the most common cancers among men, with 1.1 million cases per year worldwide.1 As current treatments,2,3 including surgery, radiotherapy, chemotherapy, and hormone therapy, result in severe side effects,4 the development of new targeted therapies with lower toxicity could significantly improve patient quality of life and potentially extend life. Moreover, neoadjuvant therapeutics effective at reducing tumor volume could potentially allow better preservation of erectile function and urinary continence in radical prostatectomy patients.2,5 Tumorigenesis WNT-4 in PCa is often dependent on aberrations in one of the key signal transduction pathways, several of which interact with the FM19G11 PIM family.6 The PIM family (proviral integration site for Moloney murine leukemia virus) consists of three serine/threonine kinases, which are known to be overexpressed in PCa, as well as breast cancer and hematological malignancies, and are often correlated with decreased overall survival (OS), resistance to therapy and cancer cell proliferation.7 PIM proteins have been implicated in driving cell growth and survival, proliferation, and avoidance of apoptosis7 by interacting with other tumorigenic pathways, such as FM19G11 the PI3K (phosphoinositide 3-kinase)/mTOR (mammalian target of rapamycin)/AKT (protein kinase B) pathway,8 as well as by influencing oncogenes and tumor suppressor genes.8 Moreover, PIM upregulation can cause resistance to conventional chemotherapy,9 radiotherapy,10 PI3K inhibitors11, and other therapeutics.12 The activity of PIM is primarily regulated at the transcriptional and protein stabilization level and is mainly influenced by the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, NF-B (nuclear factor kappa-B)8 and HSP90 (heat shock protein 90).13,14 This large repertoire of PIM signaling interactions and its implication in resistance to other treatment modalities provide a rationale for co-targeting PIM with other therapies in order to increase its efficacy. Role of PIM in prostate cancer The PIM family is composed of three highly conserved serine/threonine kinasesPIM1, PIM2, and PIM3. PIM1 has been identified to have two isoforms (33 and 44?kDa), PIM2 has three isoforms (34, 37 and 40?kDa), and PIM3 has one isoform.8 Xie et al. recommended that useful distinctions been around between your brief and lengthy isoforms of PIM1, as the 44?kDa isoform (PIM1L) is principally present in the plasma membrane. as well as the 33?kDa isoform (PIM1S) is mainly in the nucleus. PIM1L interacts using the SH3 (SRC homology 3) area from the Etk tyrosine kinase, which includes been shown to become among the sources of level of resistance to chemotherapeutic medications in PCa cell versions.15 The oncogenic potential from the PIM family is most beneficial characterized within PCa perhaps, where extensive work continues to be completed. Data can be found that suggest a job for PIM1 specifically, with higher appearance of PIM3 or PIM1 noted in PCa versus matched benign tissue in multiple cohorts.16C20 This upsurge in expression of PIM has prompted many research investigating the function of the complete PIM family members in the advancement and development of PCa.21 Interestingly, the influence of PIM on individual prognosis is disputed, as FM19G11 some reviews claim that low PIM1 expression in prostate tumor FM19G11 can be associated with poor individual outcomes.22 PIM2 and PIM1 have already been shown to are likely involved in PCa tumorigenesis, with PIM1 overexpression increasing the tumorigenicity of two PCa cell lines, DU145 and LNCaP, both in vitro and in vivo,23 while PIM2 continues to be suggested to are likely involved in prostate tumorigenesis via phosphorylation of eIF4B (eukaryotic translation initiation factor 4E).24 It has been noted that this PIM-mediated initiation of prostate tumors is weak and that the kinase family.