Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematological Cancers
Menée sur des lignées cellulaires et à l'aide de xénogreffes de leucémie myéloïde aiguë, cette étude met en évidence l'activité antitumorale d'un composé appelé LGB321, un inhibiteur des kinases PIM
Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematological cancers. Consistent with this, we found that PIMs are highly expressed in human hematological cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematological malignancies. Experimental Design: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and thus requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context. Results: LGB321 is active on PIM2-dependent Multiple Myeloma (MM) cell lines, where inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including ALL, AML, MM and NHL. Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, where modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with Cytarabine in this model. Conclusions: We have developed a potent and selective pan-PIM inhibitor with single agent anti-proliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematological malignancies.