Targeting the mutant p53 secretome.

While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.