Targeting of non-oncogene addiction

pathways control all phases of tumor development and are critical in cancer therapy as they are largely responsible for the ability of tumor cells to survive or die in response to chemotherapy and radiotherapy. The p38 MAPK signaling pathway is one of the routes that cells use extensively to interpret extracellular signals and orchestrate appropriate responses. This pathway was originally characterized as a key regulator of stress and inflammatory processes, which prompted the development of chemical inhibitors mainly targeting the p38α and p38β family members. These inhibitors were expected to curtail production of inflammatory mediators and be useful for the treatment of inflammatory diseases such as rheumatoid arthritis. Unfortunately, the available information indicates rather disappointing outcomes, sometimes due to toxicity and in other cases for lack of efficacy, notwithstanding that some clinical trial results are not made public [1]. However, recent clinical trials with p38 MAPK inhibitors have given promising results for Chronic Obstructive Pulmonary Disease [2]. Intensive research over the past two decades has provided good evidence for the implication of the p38 MAPK pathway in cellular processes unrelated to stress that are important for normal physiology. It is now clear, for example, that p38 MAPK can regulate the proliferation, differentiation and survival of many cell types. In addition, p38 MAPK signaling has been implicated in several pathologies including cancer. Initial studies performed using cell lines both in culture and in mouse xenografts indicated that this pathway can suppress tumorigenesis. More recent studies have included the use of genetically modified mice to address the role of p38 MAPK signaling in different cell types, showing that this pathway can regulate tumor development at different levels. Our group has contributed to the study of how the p38 MAPK pathway regulates tumor initiation and progression in vivo. Using mouse models, we have shown an important role of p38 MAPK signaling in colon and breast cancer [3, 4]. As reported for other tumor types, we provided evidence that the p38 MAK pathway suppresses tumor initiation in a mouse model of inflammation-associated colon tumorigenesis. Unexpectedly, once the tumor is formed, p38 MAPK signaling contributes to the proliferation and survival of Editorial the malignant cells and inhibition of p38 MAPK reduces colon tumor growth [3]. Moreover, genetic and pharmacological experiments indicate that p38 MAPK inhibition cooperates with chemotherapeutic drugs such as cisplatin to kill breast and colon cancer cells in culture and to reduce tumor …