Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo Journal Article

Authors: Wendel, H. G.; Malina, A.; Zhao, Z.; Zender, L.; Kogan, S. C.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S. W.
Article Title: Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo
Abstract: The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Eμ-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/-lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic. ©2006 American Association for Cancer Research.
Keywords: signal transduction; cancer chemotherapy; controlled study; protein expression; doxorubicin; nonhuman; animal cell; mouse; animals; mice; allele; animal tissue; drug inhibition; protein bcl 2; apoptosis; antineoplastic combined chemotherapy protocols; animal experiment; animal model; rna interference; cyclophosphamide; enzyme activation; drug resistance, neoplasm; heterozygote; phosphatidylinositol 3 kinase; protein p53; mice, inbred c57bl; carcinogenesis; genes, myc; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; lymphoma; down regulation; mammalian target of rapamycin inhibitor; drug sensitivity; rapamycin; sirolimus; protein kinase b beta; in vivo culture
Journal Title: Cancer Research
Volume: 66
Issue: 15
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2006-08-01
Start Page: 7639
End Page: 7646
Language: English
DOI: 10.1158/0008-5472.can-06-0419
PUBMED: 16885364
PROVIDER: scopus
PMCID: PMC4586049
Notes: --- - "Cited By (since 1996): 65" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus"
Citation Impact
MSK Authors