There are currently no targeted therapies against lung tumors with oncogenic K-ras mutations that are found in 25% to -40% of lung cancers and are characterized by their resistance to epidermal growth factor receptor inhibitors. The isozyme group IIa secretory phospholipase A 2 (sPLA 2 IIa) is a potential biomarker and regulator of lung cancer cell invasion; however, the relationship between K-ras mutations and sPLA 2 IIa has yet to be investigated. We hypothesize that sPLA 2 IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA 2 IIa expression in human lung tumors is increased in K-ras mutant tumors.Baseline sPLA 2 IIa expression in K-ras mutant lung cancer cell lines (A549, SW1573, H358, H2009) was assessed. Cells were treated with a specific sPLA 2 IIa inhibitor and evaluated for apoptosis and cell viability. Nuclear factor kappa-b (NF-κB) and extracellular signal-regulated kinase 1/2 activity were detected by Western blot. Human tumor samples were evaluated for sPLA 2 IIa mRNA expression by quantitative reverse-transcription polymerase chain reaction.Cytotoxicity of sPLA 2 IIa inhibition correlates with sPLA 2 IIa expression. Apoptosis in response to sPLA 2 inhibition parallels attenuation in NF-κB activity. In addition, sPLA 2 IIa expression in human tumors correlates with squamous cell pathology and increasing stage of K-ras mutant lung tumors.Baseline sPLA 2 IIa expression predicts response to sPLA 2 IIa inhibition in some K-ras mutant lung cancer cells. This finding is independent of p53 mutation status. Furthermore, squamous tumors and advanced-stage K-ras mutant tumors express more sPLA 2 IIa. These data support a role for sPLA 2 IIa as a potential global therapeutic target in the treatment of lung cancer.