Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.

TitleCabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.
Publication TypeJournal Article
Year of Publication2017
AuthorsPatnaik A, Swanson KD, Csizmadia E, Solanki A, Landon-Brace N, Gehring MP, Helenius K, Olson BM, Pyzer AR, Wang LC, Elemento O, Novak J, Thornley TB, Asara JM, Montaser L, Timmons JJ, Morgan TM, Wang Y, Levantini E, Clohessy JG, Kelly K, Pandolfi PPaolo, Rosenblatt JM, Avigan DE, Ye H, Karp JM, Signoretti S, Balk SP, Cantley LC
JournalCancer Discov
Date Published2017 07
KeywordsAnilides, Animals, Cell Line, Tumor, Cell Proliferation, Chemokine CXCL12, Heterocyclic Compounds, HMGB1 Protein, Humans, Immunity, Innate, Male, Mice, Neutrophils, Prostatic Neoplasms, Protein Kinase Inhibitors, PTEN Phosphohydrolase, Pyridines, Tumor Microenvironment, Tumor Suppressor Protein p53

Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance. This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. .

Alternate JournalCancer Discov
PubMed ID28274958
PubMed Central IDPMC5501767
Grant ListP01 CA089021 / CA / NCI NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
P50 CA180995 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States