Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells.
Richard Morgan PowellMarlies J W PeetersAnne RahbechPia AehnlichTina SeremetPer Thor StratenPublished in: Vaccines (2021)
There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8+ T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.
Keyphrases
- tyrosine kinase
- acute myeloid leukemia
- epidermal growth factor receptor
- cell cycle
- small molecule
- immune response
- cell proliferation
- cell cycle arrest
- cell death
- binding protein
- signaling pathway
- pi k akt
- pluripotent stem cells
- dendritic cells
- induced pluripotent stem cells
- nk cells
- drug delivery
- young adults
- cancer therapy
- inflammatory response