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

Wendel, H. G., Malina, A., Zhao, Z., Zender, L., Kogan, S. C., Cordon-Cardo, C., Pelletier, J., Lowe, S. W. (August 2006) Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res, 66 (15). pp. 7639-46. ISSN 0008-5472 (Print)

URL: https://www.ncbi.nlm.nih.gov/pubmed/16885364
DOI: 10.1158/0008-5472.can-06-0419

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 Emu-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.

Item Type: Paper
Uncontrolled Keywords: 1-Phosphatidylinositol 3-Kinase metabolism Animals Antineoplastic Combined Chemotherapy Protocols pharmacology Drug Resistance Neoplasm Enzyme Activation Female Genes myc Heterozygote Lymphoma drug therapy genetics metabolism Male Mice Mice, Inbred C57BL PTEN Phosphohydrolase biosynthesis genetics Proto-Oncogene Proteins c-akt metabolism Sirolimu administration dosage
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > lymphoma
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: CSHL Librarian
Date: 1 August 2006
Date Deposited: 07 Dec 2011 22:11
Last Modified: 30 Apr 2018 15:38
PMCID: PMC4586049
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22930

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