Pancreatic ductal adenocarcinoma (PDAC) is the 7th leading cause of cancer related death. Deregulation of the apoptotic pathway, including upregulation of inhibitor of apoptosis proteins (IAPs), occurs at an early stage in PDAC resulting in aggressive tumours which are often resistant to therapy. Currently, use of IAP antagonists in clinical trials aims to sensitise cancer cells to apoptosis. However, these therapies show a lack of efficacy in a large proportion of the patient population. Therefore, elucidating the molecular mechanisms associated with resistance to IAP antagonists could optimise treatment strategies for PDAC. In this study, three different screening methodologies are used to identify novel resistance drivers to IAP antagonists. Firstly, a genome-wide CRISPR-Cas9 screen was conducted to identify 1025 potential genetic contributors (p<0.05) to birinapant response in the insensitive Suit-2 cell line. Secondly, two acquired resistance cell lines from Capan-1 and Panc-1 cell lines were created from prolonged treatment exposure. Differential gene expression analysis compared acquired resistance to parental cell lines to identify 494 common gene expression changes associated with resistance (P<0.05). Finally, large scale pan-cancer drug sensitivity data sets were analysed for multi-omic resistance drivers to four IAP antagonists: birinapant, LCL161, Embelin and AZD5582. This identified significant differences between IAP antagonists, with no common drivers identified for all antagonists. The three screening methods were compared to identify three birinapant resistance drivers present in all analyses: RSU1, ACVR2A and ANK2. From these findings, initial validations of several resistance drivers were conducted. These included investigations of single target knockdowns of MYC as well as the effects of ribosome biogenesis, Estrogen signalling and proteosome regulation on IAP antagonist sensitivity. Overall, cMYC silencing and BET inhibitor combinations were the most promising combinations with IAP antagonists, with significant synergies observed in several PDAC cell lines. In summary, this project successfully utilises three methodologies to uncover several novel IAP antagonist resistance drivers and suggests several rational combination targets to improve therapeutic strategies for pancreatic cancer.