Lung cancer is the leading cause of cancer-related death. Despite the dramatic success of targeted therapies, the vast majority of lung adenocarcinoma patients are treated with platinum-based chemotherapy, although the response rate is less than 20%. Frustratingly, platinum-sensitization strategies often result in increased toxicity. To address the unmet clinical need of innate resistance to platinum-based chemotherapy in lung adenocarcinoma, we performed a genome-wide, in vitro siRNA screen for carboplatin synthetic lethality. Deconvolution screens in additional lung adenocarcinoma cell lines followed by orthogonal siRNA and pharmacologic validation of high-confidence hits identified MCL1, BCL2L1, POLG2, HDAC3 and FKBP3 as potential novel therapeutic targets. Network analysis of the primary screen data revealed highly significant enrichment for the p38 MAPK pathway, along with downstream mediators of cell cycle arrest and DNA repair. Blockade of this pathway at multiple levels was able to reverse innate platinum resistance in lung adenocarcinoma cells. These data suggest that the well-characterised role of p38 MAPKï€ signalling in mediating stress responses and cell-death in the airway and renal epithelium have been coopted by lung cancer cells as a potent mediator of chemoresistance