Abstract C56: Platinum containing anti-cancer agents as targeted therapeutics

Abstract

Abstract Cisplatin and its analogs are one of the most widely used family of cancer chemotherapeutics. However, despite a diverse array of analogs having been synthesized over the past decades, the underlying assumption has been that they all work similarly by damaging DNA. Utilizing a unique multi-platform genetic approach we show that this is not the case, and that small modifications to the core structure of cisplatin can produce unexpected changes in mechanism of action. Specifically, we found oxaliplatin and a subset of mono-functional cisplatin analogs closely resembled transcription and translation inhibitors. This set of platinum-based agents do not rely on traditional cisplatin repair and tolerance pathways such as nucleotide excision repair, homologous recombination and inter-strand cross-link repair. Instead, we've demonstrated oxaliplatin treatment kills cells by eliciting a ribosome biogenesis stress response. Additionally, across a panel of human cell lines, we've shown that higher expression of ribosomal proteins correlates with resistance to these transcription/translation inhibitor-like platinum agents. From this analysis, and by analyzing and comparing human patient tumor expression data, we've concluded that oxaliplatin treatment is best applied in tumors that have developed a heightened dependence on translation. Thus, while commonly regarded as “blunt weapons”, our current arsenal of genotoxic anti-cancer agents utilizes surprisingly diverse mechanisms that suggest new paradigms for their application in patients. Citation Format: Peter M. Bruno, Ga Young Park, Junko Murai, Yunpeng Liu, Justin Pritchard, Yves Pommier, Stephen J. Lippard, Michael T. Hemann. Platinum containing anti-cancer agents as targeted therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C56.