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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Cold Spring Harbor Laboratory; 2 Howard Hughes Medical Institute, Cold Spring Harbor, New York; 3 Department of Biochemistry and 4 McGill Cancer Center, McGill University, Montreal, Quebec, Canada; 5 University of California-San Francisco, San Francisco, California; and 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
Requests for reprints: Scott W. Lowe, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-8406; Fax: 516-367-8460; E-mail: Lowe{at}cshl.org.
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. (Cancer Res 2006; 66(15): 7639-46)
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