Title:Mechanism-based Combinations with Pim Kinase Inhibitors in Cancer Treatments
Volume: 20
Issue: 42
Author(s): Qingshan Yang, Lisa S. Chen and Varsha Gandhi
Affiliation:
Keywords:
Pim kinase inhibitor, mechanism-based combinations, transcription, translation, cell cycle, cell survival, drug resistance, parallel
pathways.
Abstract: Proviral integration site for Moloney murine leukemia virus (Pim) kinases is a potential therapeutic target in both hematological
and solid tumors, and is up-regulated in various cancer types. In certain cases, their expression levels are positively correlated with
poor clinical outcome. A number of selective Pim kinase inhibitors are under development and a few are in clinical trials. Investigations
of the mechanism of actions of these drugs have demonstrated that by inhibiting Pim kinases, processes such as transcription, translation,
cell cycle progression, cell survival and drug resistance are affected.
Pim kinases can be upregulated by multiple growth factors, cytokines, and chemokines, which also activate redundant pathways such as
phosphatidylinositide 3-kinases/protein kinase B/mammalian targets of rapamycin, and mitogen-activated protein kinases. Interestingly,
Pim kinases also share substrates with these parallel pathways. To overcome this challenge, Pim kinase inhibitors were tested in combination
with other therapeutic agents based on their unique mechanism of actions. Based on existing literature, we identified studies where
Pim kinase inhibitors were part of the combination strategies that used targeted agents or broad-spectrum chemotherapeutic drugs (including
FDA-approved agents). The addition of Pim kinase inhibitors to these treatment strategies leads to additive to synergistic cytotoxic
effect in cancer cells. Depending on the compound, combination results in sequential or complementary blockage or downregulation
of oncogenic pathway. In summary, these studies provide evidence for developing mechanism-based combination therapies with
Pim kinase inhibitors to treat cancers.
