Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells

Abstract

Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to co-administered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof-of-concept for a combination treatment which leverages both senescence and immune surveillance to therapeutic ends.

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

“…39 We next tested the apoptotic effect of VX680 via flow cytometry with an Annexin V-FITC/PI kit. The fraction of Annexin V C was defined as apoptotic cells.…”

Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models

“…Here we performed quantitative real-time PCR to determine the mRNA expression levels of more markers for senescence after treatment with 1μM MLN8237, which is comparable to the plasma concentration of MLN8237 in mice (15,21). We evaluated DEC1 (deleted in esophageal cancer 1), GLB1 (β-galactosidase1), CCNA2 (CyclinA2), CDKN1A (p21), CDKN2A (p16), IL-8, IL-6, and CXCL1 in two p53 WT (A375, Hs294T) and two p53 mut (SKMEL28, SKMEL2) melanoma cell lines in response to MLN8237 treatment.…”

“…MLN8237 is currently in clinical trials in liquid and solid tumors (12-14). We have recently shown in preclinical mouse models that combining MLN8237 with an MDM2 antagonist will activate p53-mediated apoptosis and markedly enhance the therapeutic response of p53 wild-type tumors to MLN8237 (15). …”

Combined therapies that induce senescence and stabilize p53 block melanoma growth and prompt antitumor immune responses

“…8 Specifically, we combined senescence-inducing AURKA inhibitor with an MDM2 antagonist that kills melanoma cells by stabilizing tumor suppressor p53 (Fig. 1).…”

“…The recruitment of immune cells and resultant tumor clearance was thus enhanced by combined MDM2 and AURKA antagonism in vivo. 8 The recruited immune cells included antigenpresenting dendritic cells and macrophages, as well as natural killer (NK) and T cells. We further discovered that immune cells played a critical role in the response to the regimen because the therapeutic effect was compromised in severely immune-deficient NOD/SCID interleukin-2 receptor g-chain null (NSG) mice that lack T, B, and NK cells, have functionally-defective macrophages and dendritic cells as well as defective cytokine signaling.…”