Abstract
Pemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non-small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenylate Kinase / drug effects
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Adenylate Kinase / metabolism*
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Aminoimidazole Carboxamide / analogs & derivatives*
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Aminoimidazole Carboxamide / metabolism
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Aminoimidazole Carboxamide / pharmacology
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Antineoplastic Agents / therapeutic use*
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Division / drug effects
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Enzyme Activation / drug effects
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Folic Acid Antagonists / therapeutic use*
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Glutamates / therapeutic use*
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Glycine / analogs & derivatives
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Glycine / biosynthesis
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Glycine / metabolism
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Guanine / analogs & derivatives*
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Guanine / therapeutic use
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Humans
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Kinetics
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Mesothelioma / drug therapy*
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Mesothelioma / pathology
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Pemetrexed
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Kinases / drug effects
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Protein Kinases / metabolism*
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Ribonucleotides / biosynthesis
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Ribonucleotides / metabolism*
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Ribonucleotides / pharmacology*
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TOR Serine-Threonine Kinases
Substances
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Antineoplastic Agents
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Folic Acid Antagonists
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Glutamates
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Ribonucleotides
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Pemetrexed
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phosphoribosyl-N-formylglycineamide
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Aminoimidazole Carboxamide
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Guanine
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Protein Kinases
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MTOR protein, human
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TOR Serine-Threonine Kinases
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Adenylate Kinase
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AICA ribonucleotide
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Glycine