Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer

Abstract

Intraperitoneal (i.p.) tumor dissemination and the consequent malignant ascites remain unpredictable and incurable in patients with gastrointestinal (GI) cancer, and practical advances in diagnosis and treatment are urgently needed in the clinical settings. Here, we explored tumor biological and immunological mechanisms underlying the i.p. tumor progression for establishing more effective treatments. We established mouse tumor ascites models that murine and human colorectal cancer cells were both i.p. and subcutaneously (s.c.) implanted in mice, and analyzed peritoneal exudate cells (PECs) obtained from the mice. We then evaluated anti-tumor efficacy of agents targeting the identified molecular mechanisms using the ascites models. Furthermore, we validated the clinical relevancy of the findings using peritoneal lavage fluids obtained from gastric cancer patients. I.p. tumor cells were giant with large nuclei, and highly express AURKA, but less phosphorylated TP53, as compared to s.c. tumor cells, suggesting polyploidy-like cells. The i.p. tumors impaired phagocytic activity and the consequent T-cell stimulatory activity of CD11b + Gr1 + PD1 + myeloid cells by GDF15 that is regulated by AURKA, leading to treatment resistance. Blocking AURKA with MLN8237 or siRNAs, however, abrogated the adverse events, and induced potent anti-tumor immunity in the ascites models. This treatment synergized with anti-PD1 therapy. The CD11b + PD1 + TAMs are also markedly expanded in the PECs of gastric cancer patients. These suggest AURKA is a determinant of treatment resistance of the i.p. tumors. Targeting the AURKA-GDF15 axis could be a promising strategy for improving clinical outcome in the treatment of GI cancer.

Identification of Hub genes with prognostic values in colorectal cancer by integrated bioinformatics analysis

“…AURKA has been identified as a target gene for cancer treatment, and a small molecule that targets AURKA has been found [ 38 ]. Ozawa et al showed that targeting AURKA could be a promising strategy for improving clinical outcomes in the treatment of gastrointestinal cancer [ 39 ]. Zhang et al showed that MLN8237, an inhibitor of AURKA, efficiently reduced the proliferation and motility of pancreatic ductal adenocarcinoma cells [ 40 ].…”

Identification of hub genes and its relationship with colorectal cancer patient prognosis

“…The protein AURKA is a serine/threonine kinase that regulates mitosis by activating mitosis-related proteins. Ozawa H et al showed that the targeting of AURKA may improve the clinical outcome of gastrointestinal cancer (GI) [22]. Zhang et al showed that MLN8237, an inhibitor of Aurora kinase-A, e ciently reduced the proliferation and motility of pancreatic ductal adenocarcinoma (PDAC) cells [23].…”

Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer

“…Interestingly, PD1 is also expressed in Mø in the peritoneal cavity of mice and human. Ozawa et al reported that PD1 + TAMs with dysfunctional phagocytosis are expanded in the peritoneal cavity with disseminated tumor cells in mouse CRC ascites models and GC patients (189). The peritoneal tumor cells are polyploidy (giant with large nuclei) highly expressing aurora kinase A (AURKA) and GDF15 that is partly involved in the PD1 + TAM expansion.…”