Requirement for epithelial p38α in KRAS-driven lung tumor progression
Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon et menée à l'aide de modèles murins, cette étude met en évidence le rôle de la protéine kinase p38alpha
Nearly half of the cases of lung cancer bear mutations in the RAS pathway. Unfortunately, no specific drugs are available to successfully target many RAS-driven tumors that are not surgically resectable. Despite the sound rationale for targeting oncogene products for cancer therapeutics, this often leads to development of resistance. As an alternative, nononcogenic proteins can sometimes facilitate tumor progression, and, even though they are neither mutated nor overexpressed in the malignant cells, they may represent potential targets for anticancer therapies. We have found that nononcogenic signaling through p38α plays a tumor-promoting function in lung adenocarcinoma epithelial cells by inducing the expression of TIMP-1, a growth factor-like protein. We propose that p38α inhibition could be therapeutically useful.Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.