A review on PIM kinases in tumors

Abstract

The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is serine/threonine kinases that promote growth and survival in multiple cell types, implicated in the pathogenesis of various diseases. Over expression of Pim-1 experimentally leads to tumor formation in mice, whereas there is no observable phenotype concerning the complete knockout of the protein. When it is over expressed it may lead to cancer development by three major ways; by inhibiting apoptosis, by promoting cell proliferation and also through promoting genomic instability. Expression in normal tissues is nearly undetectable. Recent improvements in the development of novel inhibitors of PIMs have been reviewed. Significant progress in the design of PIMs inhibitors, in which it displays selectivity versus other kinases, has been achieved within the last years. However, the development of isoform-selective PIM inhibitors is still an open task. As Pim-1 possesses oncogenic functions and is over expressed in various kinds of cancer diseases, its inhibition provides a new option in cancer therapy. A PubMed literature search was performed to review the currently available data on Pim-1 expression, regulation, and targets; its implication in different types of cancer and its impact on prognosis is described. Consequently, designing new inhibitors of PIMs is now a very active area of research in academic and industrial laboratories.

Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

“…Activated PIM kinases have been identified in many types of cancer including haematological malignancies such as myeloid and lymphoblastic leukaemias and solid epithelial tumours such as prostate and pancreatic cancer (Amson et al, 1989;Dhanasekaran et al, 2001;Arrouchi et al, 2019a). The PIM1 gene was initially identified via insertion of the proviral integration sites in Moloney murine leukaemia virus (MMLV)induced lymphomas which resulted in over 50% of T-cell lymphomas displaying integration near to the PIM locus (Cuypers et al, 1984).…”

High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms

“…Protein kinases regulate many cellular signaling pathways, and their disruption is often associated with carcinogenesis [9]. Although dysregulations of the NEK2, PIM1, and PIM3 kinase signaling axes have been implicated in the pathogenesis of several cancers [10,11], including those with a neuroendocrine phenotype [12,13], their role in the pathogenesis of BP-NENs has not been determined.…”

“…The PIM family, composed of three isoforms, viz. PIM1-3, plays a key role in the control of cell proliferation, survival, and migration [11].…”

“…PIM1 kinase can contribute to tumorigenesis also by enhancing MYC-regulated oncogenic signaling pathways [18]. Moreover, PIM1 has been found to be associated with drug resistance of cancer cells [11,19]. PIM1 is mainly expressed in the thymus, spleen, bone marrow, fetal liver, and other hematopoietic organs, while its expression is absent in adult tissues [11,20].…”

“…Moreover, PIM1 has been found to be associated with drug resistance of cancer cells [11,19]. PIM1 is mainly expressed in the thymus, spleen, bone marrow, fetal liver, and other hematopoietic organs, while its expression is absent in adult tissues [11,20]. Abnormal expression of PIM1 has been linked to hematological malignancies [20,21], colon [22], bladder [23], head and neck squamous cell carcinoma [24], and prostate cancer [25,26], including the neuroendocrine variant: one of its most aggressive forms [13].…”