A Selective PIM Kinase Inhibitor Is Highly Active In Multiple Myeloma: The Biology of Single Agent and PI3K/AKT/mTOR Combination Activity

Abstract 3001

PIM kinases co-regulate several important elements of the PI3K/AKT/mTOR pathway in myeloma cells (Munugalavadla V. et al., ASH 2010 submitted abstr.). In this study we show that pan-PIM inhibition suppresses growth in myeloma cell lines, xenografts, and primary patient samples, both as a single-agent as well acting synergistically in combination with PI3K, AKT, and mTOR inhibition. The PIM kinases are a family of 3 ser/thr growth factor- & cytokine-induced proteins hypothesized to have redundant survival and growth functions. Although PIM-1,2 have been noted as highly expressed in myeloma (Claudio et al., 2002), there are few data to support potential therapeutic utility of PIM inhibition in this indication. We show myeloma cell lines express all 6 PIM protein isoforms to varying extents, and we describe the properties of a novel pan-PIM inhibitor GNE-652 with picomolar biochemical potency, an excellent selectivity profile, and favorable ADME properties. Myeloma cell lines exhibit a striking prevalence of response to GNE-652 (23 of 25 lines with IC50 < 1 micromolar, median < 0.1 micromolar) and synergy in combination with the PI3K inhibitor GDC-0941 (mean combination index values ~0.2 (n=25)). We used an unrelated compound GNE-568 which has a PIM-1,3 selective profile to test the hypothesis that PIM-2 may have a non-redundant role in myeloma cells. GNE-568 while having cellular potency against PIM-1 and PIM-3, did not have single agent activity in myeloma cell lines nor did it act synergistically with GDC-0941 (n=10 cell lines). Interestingly, PI3K and AKT inhibitors showed the greatest extent of synergy with GNE-652, whereas mTOR-selective inhibitors were synergistic to a lesser extent. Standard of care agents dexamethasone, revlimid, velcade, and melphalan also combined well with GNE-652, but to a lesser extent and not as broadly. The synergistic anti-tumor activity of GNE-652 and PI3K inhibitor GDC-0941 on cell lines or on primary myeloma bone marrow aspirates in vitro was associated with cell-cycle arrest and marked apoptosis. In addition, we found 4 of 4 myeloma xenograft mouse models tested with GNE-562 and GDC-0941 showed excellent combination efficacy that correlated with modulation of the expected pharmacodynamic markers. These results provide the rationale for further preclinical development of PIM inhibitors and provide the basis for a possible clinical development plan in multiple myeloma.