Targeting p38MAPK in the tumor stroma for lung cancer therapy

Lung cancer has been associated with the highest rate of cancer-related deaths worldwide. Although major advances have been made in understanding this disease, including the identification of novel potential therapeutic targets, overall survival has not significantly changed over the past several decades. It is becoming clear that the most effective approach for treating lung cancer requires therapies that target both tumor cells and the tumor microenvironment. In this respect, stromal fibroblasts could be attractive targets, because they are known to provide additional signals to support tumor growth, survival, and drug resistance. Unfortunately, no treatment option exists that successfully targets this component of the tumor microenvironment. We identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, pro-tumorigenic signal in the tissue microenvironment. Systemic downregulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38MAPK in stromal fibroblasts has a significant tumor suppressive effect on K-ras lung tumorigenesis. We identify fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to Carcinoma-Associated Fibroblasts (CAF), and cancer cell proliferation. Furthermore, both K-ras-driven mouse lung tumors and orthotopically-grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that the hyaluronan cancer niche plays a major role in driving lung tumorigenesis and that chemical inhibition of p38MAPK or hyaluronan synthesis could provide an important improvement for lung cancer treatment.