| Autor: |
Matthew T. Burger, Jocelyn Holash, Richard Zang, J. Alex Aycinena, Cornelia Bellamacina, Mika Lindvall, Gisele Nishiguchi, Jiong Lan, Wooseok Han, Christopher Wilson, Joerg Trappe, Peter Drueckes, Estelle Pfister, Audrey Kauffmann, Christine Fritsch, Tiffany Tsang, Jamie Narberes, Robert Warne, Paul Feucht, Michael Doyle, Jianjun Yu, Julie Chan, Stephen Basham, Xiao-Hong Niu, Jing Lu, Yumin Dai, Tatiana Zavorotinskaya, Marjorie Ison, Christie Fanton, Joseph Castillo, Min Chen, Yingyun Wang, John L. Langowski, Pablo D. Garcia |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6522398 |
| Popis: |
Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic 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 hematologic 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 cell lines, where it 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 acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which 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 antiproliferative 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 hematologic malignancies. Clin Cancer Res; 20(7); 1834–45. ©2014 AACR. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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