LB900 Role of p38β in cutaneous T cell lymphoma

Abstract

Cutaneous T cell lymphoma (CTCL) is an incurable cancer; understanding its underlying molecular mechanisms may unlock a cure. In patient samples of CTCL, we observed a significant increase in gene expression of p38β while that of p38α decreased, compared to normal healthy CD4+ T cells. This prompted us to further dissect the role of p38β in CTCL to inform the application of small molecule inhibitors that specifically target p38β. Current well-developed small molecule p38 inhibitors target both p38α as well as p38β, as they share ∼80% structural similarity. However, multiple clinical trials have shown adverse effects and development of drug resistance when patients with cancer are treated with potent p38 inhibitors alone. Such side effects likely occur because p38α is an essential protein in many cell types; indeed, p38α gene knock-out mice exhibit embryonic lethality. Therefore, any prolonged treatment using p38α inhibition may cause adverse effects. Using Hut78 CTCL cells in which we silenced p38β using lentiviral siRNA, we tested for possible mechanisms of drug resistance that could explain why patients who participated in p38α/β inhibitor clinical trials experience adverse effects. Gene silencing of p38β in Hut78 cells did not decrease cell proliferation; instead, proliferation slightly increased compared to that of WT cells. This aligned with increased IL-17 RA and p38γ which is a driver for cell proliferation in Hut78 cells. Our hypothesis is that p38β-depleted CTCL cells increase survival by elevating the MAPK12-NFAT-IL17 signaling pathway axis, which increases proliferation and propagandas inflammation in the surrounding regions resulting in drug resistance and adverse effects. We used confocal immuno-fluorescence microscopy analyses of p38β-depleted Hut78 cells to reveal a novel molecular mechanism, in which depleting p38β offset cytoskeleton formation in the cytosol. This suggests p38β is important for maintaining the shape or frame of CTCL cells, and may explain why CTCL, a malignant T cell, infiltrate skin, from which novel revenues of drug development may be invented that are complementary to p38β inhibition.