Background Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. (SCC9, SCC25) cell lines, metformin enhanced gefitinib cytotoxicity only in LKB1 conveying cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments. Furthermore, the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy Lappaconite Hydrobromide that is usually often induced during metabolic stress inhibiting cell death. Conclusion/Significance Thus, targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatins ability to synergize with gefitinib in SCC cells. Introduction A fundamental requirement of all cells is usually the ability to adapt to changes in their environment that includes the availability of nutrients required to maintain homeostasis or to trigger proliferation only when they are in sufficient supply , . Under conditions of metabolic stress where nutrients are limited, a number of cellular stress pathways can be activated that attempt to alleviate this stress or if the stress cannot be overcome to induce apoptosis , , . Common downstream targets of these pathways include the inhibition of protein translation, which is usually the major energy consumption process within cells, and the induction of cell cycle arrest to prevent cell proliferation , , . Glucose deprivation, hypoxia, amino acid starvation, growth factor withdrawal and conditions or brokers that affect ATP synthesis are all common causes of metabolic stress , Lappaconite Hydrobromide . A Lappaconite Hydrobromide number of signaling pathways regulate the cellular response to these stressors including the Integrated Stress Response (ISR) , , growth factor signaling , Lappaconite Hydrobromide  and the Liver Kinase W1 (LKB1)/AMP-Activated Protein Kinase (AMPK) pathway that is usually a sensor of cellular energy (ATP) levels , , . Malignant cells are dependent on the sustained availability of the end products of the mevalonate pathway that include de novo cholesterol and isoprenoids , . The statin family of drugs are potent inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase that hole to the active site of HMG-CoA reductase with up to a 1000x higher affinity than its natural substrate . Through inhibition of mevalonate synthesis, statin treatment has the potential for plieotropic cellular effects through the targeting of a wide variety of cell signaling proteins , , . We have previously shown that lovastatin can induce tumour specific apoptosis especially in squamous cell carcinomas (SCC)  and that 23% of SCC patients treated with lovastatin as a single agent showed disease stabilization in our Phase I clinical trial . To enhance efficacy, understanding the KCY antibody mechanism of lovastatin-induced apoptosis may uncover novel therapeutic strategies. To this end, we have recently exhibited that the ability of lovastatin to induce metabolic stress responses in SCC cells through the induction of the ISR  and inhibition of ligand induced activation of the epidermal growth factor receptor (EGFR) . Both pathways play Lappaconite Hydrobromide key functions in regulating lovastatin-induced apoptosis in SCC cells. A variety of defined cell stresses commonly lead to the phosphorylation of eukaryotic initiation factor (eIF) 2 shutting down global protein translation and inhibiting cell proliferation to potentially alleviate the stress known as the ISR . The subunit of eIF2 is usually the target of a family of serine or threonine kinases that are activated by different forms of environmental and metabolic tensions that includes the General Control Non-repressed 2 (GCN2) gene induced by amino acid starvation . Depending on the strength of the stress stimulus, ISR induction can either alleviate the stress or alternatively induce apoptosis. Enhanced manifestation of the transcription factors activating transcription factor (ATF) ATF3 and C/EBP-homologue protein (CHOP) can mediate this apoptotic response , . Activation of the EGFR in epithelial cells and their derived tumours including SCC is usually stimulated by ligand binding that is usually required to activate its downstream signaling targets that mediate its effects on growth, metabolic activity and cell survival , , . EGFR autophosphorylation sites when activated by ligand binding are the biochemical causes that start a series of downstream.