The Potential and Limitations of p38MAPK as a Drug Target for the Treatment of Hematological Malignancies

Abstract

The classical role of p38MAPK involves the transmission of death signals from stress stimuli such as ionizing radiation, inflammation and chemotherapy in normal and malignant cells. However emerging evidence point to it having pleiotropic functions, ranging from cellular proliferation and survival, to cell cycle arrest and regulation of the tumor microenvironment. The mechanisms responsible for these diverse and rather contradictory functions of p38MAPK are only now being unraveled. In some hematological malignancies, p38MAPK is constitutively activated. The reasons for this are not fully understood, but can result from underlying genetic lesions such as the bcr/abl translocation. The involvement of p38MAPK in mediating cell cycle arrest in the face of cytotoxic damage suggests that p38MAPK may be a therapeutic target. The role of p38MAPK in cytokine production by the stromal compartment adds another level of complexity to the regulation of hematological malignancies that exhibit a degree of stromal dependence, at least some of which is cytokine driven. p38MAPK dependent cytokine production by malignant hematopoietic cells has also been observed, and promotes tumor cell adhesion, angiogenesis and osteoclastogenesis. This suggests a mutual relationship between tumor and stromal cells. In contrast, p38MAPK is required for the effects of cytotoxic agents in some hematological malignancies. These conflicting qualities point to the importance of careful consideration of the use of p38MAPK inhibitors as a therapeutic strategy.