Abstract
The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.
Highlights
The proviral insertion in murine leukemia virus (PIM) family proteins are serine/threonine kinases that promote growth and survival in multiple cell types [1,2,3]
PIM1 and PIM2 previously were reported among genes whose expression is higher in ABC-DLBCL, helping to distinguish it from germinal-center B-cell (GCB) subtype [17]
We compared the activity of PIM447 to AZD1208 [19], the only other pan-PIM kinase inhibitor to have entered clinical evaluation, and found a similar pattern of activity against ABC-DLBCL cell lines, though AZD1208 was less active against Riva and U2932 and more active against TMD8 (Figure 1D)
Summary
The proviral insertion in murine leukemia virus (PIM) family proteins are serine/threonine kinases that promote growth and survival in multiple cell types [1,2,3]. The PIMs are found expressed in cells throughout hematopoietic cell lineages [7, 8] and in multiple other cell types, including vascular smooth muscle [9], cardiomyocytes [10], and breast [11]. They are constitutively active kinases regulated through expression and rapid turnover downstream of growth factor signaling [12, 13]. Their pro-growth and survival endpoints, direct and indirect, include activation of cap-dependent protein translation initiation, progression through the cell cycle, and inhibition of apoptosis, among others [1,2,3]
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