Targeting the Pim kinases in multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

“…PIM-2 overexpression in colorectal cancer cells led to increased glycolysis and energy production (16). In addition, inhibition of PIM-2 kinase significantly reduced the growth of multiple myeloma cells (6,17). This mechanism is thought to occur in part by PIM-2 phosphorylating TSC2, a negative regulator of mTORC1.…”

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

“…Since currently there are no approved STAT3 inhibitors in clinical use, PIM inhibition merits further investigation in lung cancer as well as other tumor types. AZD1208 is not in clinical development any more [22] and we plan to extend the current work using the pan-PIM inhibitor LGH447 (PIM447). LGH447 has single agent activity, and blocks resistance pathways when combined with standard of care treatments [22,[36][37][38] .…”

“…Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase, involved in cell cycle progression, cell growth, cell survival and therapy resistance. PIM-1 is activated in various types of cancer, amongst which prostate [14][15][16] , colorectal [15,[17][18][19] , triple negative breast cancer (TNBC) [20,21] , hematologic malignancies [22][23][24] , neuroblastoma [25] and lung cancer [26] . For this reason, PIM kinases could provide a common target for the treatment of diverse malignancies.…”

The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

“…Pre‐clinical studies in CLL (Chen et al , 2009c; Decker et al , ; Cervantes‐Gomez et al , ), other haematological malignancies (Garcia et al , ; Keane et al , ; Brunen et al , ; Nair et al , ; Paino et al , ) and solid tumours (Chen et al , 2009b, ; Foulks et al , ; Braso‐Maristany et al , ; O'Hayer et al , ; Warfel et al , ), suggest that, owing to their important roles in tumour cell biology, the PIM family of kinases may represent targets for novel, single agent or combination therapies. This concept is illustrated by a recent study in which the combination of a PIM and a PI3 kinase inhibitor, NMS‐P645 and GDC‐0941 respectively, had significantly more anti‐proliferative activity than either inhibitor alone against pancreatic cancer cells (Mologni et al , ).…”