Targeting MXD1 sensitises pancreatic cancer to trametinib
Background The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear. Objective We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC. Design We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism. Results We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation
