Reversing drug resistance in vivo.
Apoptotic defects occur in oncogenesis and contribute to drug resistance. We have shown that Bcl-2, Akt, and the translational regulator eIF4E cooperate with Myc during lymphomagenesis and are potent inducers of drug resistance. Interestingly, lymphomas expressing Akt, but not those expressing Bcl-2 are sensitized to chemotherapy-induced apoptosis by the mTOR inhibitor rapamycin, an effect that is countered by eIF4E. These results provide in vivo validation for a strategy to reverse drug resistance in human cancers and highlight the potential role of translational deregulation in oncogenesis and resistance. They also illustrate the importance of tailoring cancer therapy based on tumor genotype.
Wendel
Hans-Guido
HG
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Lowe
Scott W
SW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D039561:Eukaryotic Initiation Factor-4E; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus