Abstract 2730: RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition

Abstract

Abstract The molecular chaperone heat shock protein 90 (HSP90) maintains the conformation, stability and function of oncogenic client proteins, many of which are mutated or overexpressed. Therefore, HSP90 is an important cancer therapeutic target. To further increase the efficacy of HSP90 inhibitors, combinatorial therapeutic strategies may be beneficial. Here we report an unbiased global screening approach to identify genes that encode potentially druggable proteins that modulate cellular responses to HSP90 inhibition. From the 7,593 genes that were tested, three components of the anaphase-promoting complex (APC/C) were among the genes which when silenced caused significant HSP90 inhibitor sensitisation. siRNA knockdown of ANAPC1, -8 or -4 produced up to three-fold sensitisation to HSP90 inhibitors 17-AAG and AUY922 in human colon cancer cells. Intriguingly, we show that combinatorial siRNA-mediated ANAPC1 knockdown and HSP90 inhibition induced an accumulation of mitotic cells exhibiting a tri-polar spindle formation. A marked increase in cyclin B1 and aurora A protein levels was observed in response to combinatorial ANAPC1 knockdown and HSP90 inhibition. These effects may have been responsible for the observed formation of aberrations in the mitotic spindle architecture. Furthermore, after a period of prolonged mitotic arrest, cancer cells treated with combinational ANAPC1 knockdown and HSP90 inhibition were committed to apoptosis. Mimicking siRNA knockdown, treatment with the APC/C inhibitor proTAME synergistically sensitised human colon carcinoma cells to HSP90 inhibition. These exciting results provide a mechanistic explanation underlying the HSP90 inhibitor sensitisation phenotype, and suggest that the APC/C may represent an interesting therapeutic target to exploit in combination with HSP90 inhibitors. Furthermore, therapeutic approaches may be developed which exploit the vulnerability of mitotic cancer cells in the context of HSP90 inhibition. Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Costas Mitsopoulos, Bissan Al-Lazikani, Spiros Linardopoulos, Paul Clarke, Paul Workman. RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2014-2730