Targeting the mutant p53 secretome

Abstract

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.

Figure 1. Targeting downstream effects of mutant p53.

Mutant p53 dysregulates multiple downstream pathways in cancer cells, promoting resistance to apoptosis, bypass of cell cycle checkpoints, defective DNA repair, and angiogenesis, as well as a secretion axis that is regulated by suppression of miR-34a expression. The output of this secretome involves RAB6A⁺ vesicle-mediated extracellular release of insulin-like growth factor binding protein-2 (IGFBP2) and osteopontin/secreted phosphoprotein 1 (osteopontin/SPP-1) through Golgi reassembly-stacking protein 55/GOLGIN45/myosin IIA (GRASP55/GOLGIN45/MYOIIA). As compared with theoretical targeting of other downstream pathways, GRASPIN, a small molecule inhibitor of GRASP55, prevents GRASP55 from binding with GOLGIN45 and consequently can inhibit this secretory axis (9). BCL2, B cell lymphoma 2; CDK, cyclin-dependent kinase; DDR, DNA damage response; MCL1, myeloid cell leukemia 1.