Data from Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematologic Cancers

• DOI: 10.1158/1078-0432.c.6522398
• Publication Date: 2023-04-01T07:48:57Z
• Authors: Pablo D. Garcia; John L. Langowski; Yingyun Wang; Min Chen; Joseph Castillo; Christie Fanton; Marjorie Ison; Tatiana Zavorotin...; Yumin Dai; Jing Lu; Xiao-Hong Niu; Stephen Basham; Julie Chan; Jianjun Yu; Michael Doyle; Paul Feucht; Robert Warne; Jamie Narberes; Tiffany Tsang; Christine Fritsch; Audrey Kauffmann; Estelle Pfister; Peter Drueckes; Joerg Trappe; Christopher Wilson; Wooseok Han; Jiong Lan; Gisele Nishiguchi; Mika Lindvall; Cornelia Bellamacina; J. Alex Aycinena; Richard Zang; Jocelyn Holash; Matthew T. Burger

<div>Abstract<p><b>Purpose:</b> PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies.</p><p><b>Experimental Design:</b> Pan-PIM proven difficult develop because PIM2 low <i>K</i><sub>m</sub> for ATP and, thus, requires very potent inhibitor effectively block the kinase activity at levels cells. We developed specific pan-PIM inhibitor, LGB321, which is active on cellular context.</p><p><b>Results:</b> LGB321 PIM2-dependent myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling phosphorylation BAD. Broad cancer line profiling demonstrates limited lines derived from solid tumors. In contrast, significant diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), myelogenous (AML), non-Hodgkin lymphoma (NHL). Furthermore, demonstrate KG-1 AML xenograft model, modulation pharmacodynamics markers predictive efficacy. Finally, synergizes cytarabine this model.</p><p><b>Conclusions:</b> selective single-agent antiproliferative an model. Our results strongly support development treat malignancies. <i>Clin Cancer Res; 20(7); 1834–45. ©2014 AACR</i>.</p></div>