The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target; therefore, identifying druggable synthetic lethal interactions in MYC‐active PDAC may lead to novel precise therapies. First, to identify networks with hyperactive MYC, we profiled transcriptomes of established human cell lines, murine primary PDAC cell lines, and accessed publicly available repositories to analyze transcriptomes of primary human PDAC. Networks active in MYC‐hyperactive subtypes were analyzed by gene set enrichment analysis. Next, we performed an unbiased pharmacological screen to define MYC‐associated vulnerabilities. Hits were validated by analysis of drug response repositories and genetic gain‐ and loss‐of‐function experiments. In these experiments, we discovered that the proteasome inhibitor bortezomib triggers a MYC‐associated vulnerability. In addition, by integrating publicly available data, we found the unfolded protein response as a signature connected to MYC. Furthermore, increased sensitivity of MYC‐hyperactive PDACs to bortezomib was validated in genetically modified PDAC cells. In sum, we provide evidence that perturbing the ubiquitin–proteasome system (UPS) might be an option to target MYC‐hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the UPS as a subtype‐specific therapeutic approach.