PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Abstract

PIM kinases have 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. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors 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.

Fig. 1. Categories of therapeutics that could be used in combination with PIM inhibition in prostate cancer.

Outer boxes: therapies that are well developed for prostate cancer but that could benefit from the PIM co-targeted inhibition approach. Inner boxes: related targets and specific drugs that are currently under development. Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.

Fig. 2. Key interactions between PIM kinases and targetable signaling pathways.

In prostate cancer, the key targetable pathways that interact closely with PIM signaling are the JAK/STAT and PI3K pathways. Abbreviations: 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; AKT, protein kinase B; BAD, Bcl2-associated death promoter; BCL2, B-cell CLL/lymphoma 2; eIF-4E, eukaryotic translation initiation factor 4E; JAK, Janus kinase; mTOR, mammalian target of rapamycin; MYC, avian myelocytomatosis viral oncogene homolog; PDK1, pyruvate dehydrogenase kinase 1; PI3K, phosphoinositide 3-kinase; PIM, proviral integration site for Moloney murine leukemia virus; PRAS40, proline-rich Akt substrate, 40 KDa; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; STAT, signal transducer and activator of transcription; TSC, tuberous sclerosis complex.