Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy.

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.

Cyclo-oxygenase-2 expression in primary cancers of the lung and bladder compared to normal adjacent tissue.

Multiple observations in the laboratory and the clinical setting have linked expression of the enzyme cyclo-oxygenase-2 (COX-2) to carcinogenesis. The frequency and amount of COX-2 and Bcl-2 expression in primary lung and bladder cancer sites were detennined by immunoblot analysis of cell lysates prepared from frozen human tumor tissue and matched normal adjacent tissue. COX-2 protein was expressed statistically more frequently and at a higher level in primary adenocarcinomas and squamous cell carcinomas of the lung as well as transitional cell carcinomas of the bladder than in normal adjacent tissue. No correlation was observed between COX-2 and Bcl-2 expression in either the lung or bladder cancer specimens. Immunohistochemistry was also employed to localize COX-2 expression. In addition to expression in the malignant tissues, COX-2 was occasionally localized to the normal bronchial and transitional cell epithelia of the normal adjacent tissue. Detection of COX-2 in histologically normal appearing adjacent tissue suggests that COX-2 may be involved in early cellular changes leading to the development of lung and bladder cancer.