Individual 2 was a 68-year-old girl with an intra-abdominal hilar and mass lymph node involvement, and was treatment na also?ve before trial enrollment. are wild-type for both and wild-type melanoma. Through mechanistic research, we demonstrate a job for autophagy induction within the reaction to the AKT inhibitor/chemotherapy mixture and claim that autophagy inhibitors could be one technique to enhance efficacy in the clinical setting. mutations (Chapman et al., 2011; Flaherty et al., 2010; Hauschild et al., 2012). In randomized phase III clinical Oxiracetam trials, treatment with the BRAF inhibitor vemurafenib is usually associated with significant levels of tumor shrinkage and a progression-free survival of 6.8 months (Chapman et al., 2011). Although resistance is Oxiracetam nearly inevitable, small numbers of patients have been identified who show prolonged (>3 year) responses to single-agent BRAF inhibitor therapy (Kim et al., 2012). Resistance to BRAF inhibitors is usually complex, multi-factorial, and typically dependent upon reactivation of the MAPK signaling pathway (Fedorenko et al., 2011). The importance of MAPK pathway signaling recovery was exhibited in phase II Oxiracetam clinical trials in which the combination of a BRAF inhibitor with a MEK inhibitor significantly increased progression-free survival compared to BRAF inhibitor alone (Infante et al., 2011; Paraiso et al., 2010). Despite the significant improvements in systemic melanoma therapy, few effective targeted therapy options are available for the 50% ITGB2 of melanoma patients whose tumors lack activating mutations. One significant group of WT melanoma, accounting for 15C20% of all cutaneous melanomas, are those harboring activating mutations (Devitt et al., 2011; Fedorenko et al., 2012). Highly potent allosteric inhibitors of MEK are currently being evaluated in mutant melanoma (Ascierto et al., 2013). In recent phase II clinical trials, the MEK inhibitor MEK162 was associated with a response rate of 20% in mutant melanoma with a median PFS of 3.6 months (Ascierto et al., 2013). Combination strategies for mutant melanoma are being actively explored. The remaining 30% of all melanomas are wild-type for both and WT melanoma are therefore urgently needed. A large number of studies support a role for phospho-inositide-3-kinase (PI3K)/AKT signaling in the development and progression of melanoma (Madhunapantula and Robertson, 2009). Upon activation, PI3K phosphorylates phosphotidylinositol-4,5, biphosphate (PIP2) to PIP3, which in turn activates the downstream kinases PDK1 and AKT. Of these, AKT plays a critical role in survival through the phosphorylation of BAD as well as the regulation of cell cycle entry by phosphorylating and inactivating glycogen-3 synthase kinase (GSK3)-, leading to the modulation of cyclin D1 (Diehl et al., 1998; Frame and Cohen, 2001). PI3K/AKT signaling also has important downstream effects upon protein turnover and cell glucose metabolism via the regulation of the mTOR/S6K and GSK3 signaling pathways. Despite single agent PI3K inhibition having little effect upon melanoma growth and survival, there is evidence that PI3K targeted brokers enhance the efficacy of MEK inhibition in both and studies (Bedogni et al., 2004; Jaiswal et al., 2009; Posch et al., 2013; Smalley et al., 2006). Autophagy is an adaptive response to metabolic and drug-induced stress that involves the sequestration, lysosomal degradation and recycling of organelles and proteins (Mathew et al., 2007). Although the induction of autophagy constitutes an important mechanism of cell survival, persistent or high-level autophagy can lead to the depletion of key organelles and the activation of caspase-dependent apoptosis (Lum et al., 2005; Mathew et al., 2007; Tormo et al., 2009). Autophagy thus plays a complex, context-specific, role in cancer development that is often contradictory, with studies linking autophagy to both oncogenic transformation as well as tumor suppression.