Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells.
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 wild-type 53. In the model studied, this effect is accompanied by 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 coadministered 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 that leverages both senescence and immune surveillance to therapeutic ends.
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Anna E
AE
Vilgelm
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jeff S
JS
Pawlikowski
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Yan
Y
Liu
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Oriana E
OE
Hawkins
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Tyler A
TA
Davis
Meharry Medical College, Nashville, Tennessee.
Jessica
J
Smith
Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, Tennessee.
Kevin P
KP
Weller
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Linda W
LW
Horton
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Colt M
CM
McClain
Division of Cancer Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
Gregory D
GD
Ayers
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
David C
DC
Turner
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
David C
DC
Essaka
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
Clinton F
CF
Stewart
Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Jeffrey A
JA
Sosman
Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Mark C
MC
Kelley
Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.
Jeffrey A
JA
Ecsedy
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jeffrey N
JN
Johnston
Tennessee Valley Healthcare System, Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. ann.richmond@vanderbilt.edu.
Ann
A
Richmond
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology
D001381:Azepines; D007093:Imidazoles; C550258:MLN 8237; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C482205:nutlin 3; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D064096:Aurora Kinase A