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Acquired cellular resistance to traditional chemotherapeutics is a common obstacle in the treatment of most cancer cell types. This resistance occurs as a result of changes in the underlying molecular mechanisms of disease progression. The development of novel chemotherapeutic approaches designed to enhance the efficacy of protypical anti-cancer drugs is important in order to overcome this issue. Such approaches will aid in understanding the biomolecular phenomena responsible for drug resistance and disease progression. Combining signaling pathway inhibitors has become an effective strategy for enhancing tumor cell death by targeting multiple pathways known to regulate cell survival. Pemetrexed, an FDA-approved anti-folate drug, targets thymidylate synthase (TS) and a secondary folate-dependent enzyme, 5’ aminoimidazole-carboximide ribonucleotide formyltransferase (AICART); both important for DNA synthesis. Studies performed by our collaborator demonstrated that TS inhibition causes intracellular accumulation of ZMP+ and activation of AMPK which is known to induce autophagy in mammalian cells. Previous studies from our lab and others showed that sorafenib, a multi-kinase inhibitor of Raf-1 and class III receptor tyrosine kinases, was able to induce a cytotoxic form of autophagy in a variety of tumor cell types. Combination treatment using pemetrexed and sorafenib in these cancer cells resulted in an enhancement of autophagy and cell lethality beyond that of individual drugs alone. Inhibition of autophagy suppressed the toxic interactions of these drugs in all cell types examined. Pemetrexed/sorafenib cotherapy also proved to be an effective treatment for triple negative breast cancer cells having advanced to a stage of estrogen independence. Fulvestrant-resistant MCF7 cells were more sensitive to the drug combination than parental, estrogen-dependent MCF7 cells. Breast cancer cells cotreated with pemetrexed and sorafenib exhibited enhanced MEK/ERK signaling, Src activation that was dependent on platelet-derived growth factor β (PDGFRβ) downregulation, elevated protein phosphatase 2A (PP2A) activity, and increased de novo ceramide synthesis. Studies using a mouse model of experimentally-induced breast cancer validated drug combination effectiveness through inhibition of tumor growth, while no deleterious effects on normal tissues were observed. The data presented demonstrates that pemetrexed/sorafenib cotreatment augments chemosensitivity in both in vitro and in vivo systems. Based upon these findings, a Phase I clinical trial involving pemetrexed and sorafenib in breast cancer patients with solid, recurrent tumors was begun in 2011. In conclusion, this work strongly supports a promising therapeutic utility for the pemetrexed/sorafenib combination in treatment of various cancer cell types.