Importantly, some of the same pathways that block apoptosis during tumorigenesis also impinge on the apoptotic response to chemotherapeutic drugs

Importantly, some of the same pathways that block apoptosis during tumorigenesis also impinge on the apoptotic response to chemotherapeutic drugs. 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 (and loss of 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 Velneperit 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. Introduction Tumorigenesis involves a series of genetic events that disrupt or alter signaling networks controlling proliferation and survival. The precise order of genetic alterations and their combinations that can confer malignant characteristics is variable, thereby producing heterogeneity in tumor behavior. As one example, increased oncogenic signals activate tumor suppressor programs, including apoptosis and senescence, and their disruption is an obligate requirement during tumorigenesis (1, 2). Disruption of apoptotic programs in tumor development can occur in different ways, for example through loss of tumor suppressor genes like and (3) and survival pathways like the phosphatidylinositol-3-OH Velneperit kinase [PI(3)K] pathway or its effectors and (4C6). Importantly, some of the Velneperit same pathways that block apoptosis during tumorigenesis also impinge on the apoptotic response to chemotherapeutic drugs. Thus, the nature of the genetic lesions incurred during tumorigenesis to disrupt apoptosis can influence treatment behavior to varying degrees (4, 7C10). Conversely, strategies to restore apoptosis to tumor cells, either by increasing proapoptotic signals, suppressing prosurvival signals, or by simultaneously achieving both, may prove effective for treating otherwise refractory tumors. The PI(3)K pathway is implicated in cellular transformation and tumor development and contributes to the oncogenic activities of and [reviewed in ref. 11]. Concordantly, deregulation of this pathway is observed in many cancers, including lymphoma and leukemia, and most often involves inactivation of the negative regulator (refs. 12C14; reviewed in ref. Rabbit polyclonal to CUL5 15). Also, heterozygous mice develop tumors in multiple tissues, sometimes in the absence of complete PTEN inactivation, indicating that in certain contexts can be haploinsufficient for tumor suppression (16C19). Activation of the PI(3)K pathway has myriad effects on cellular physiology by virtue of its ability to regulate effectors controlling translation, metabolism, and cell survival (20C25). Although it seems likely that all of these properties contribute to Velneperit tumorigenesis and drug resistance, the ability of deregulated PI(3)K signaling to promote cell survival seems particularly important (4). Owing to its gain-of-function mode of action, the PI(3)K pathway represents an attractive therapeutic target, and compounds targeting multiple components of the pathway are in preclinical and clinical development (26). One drug that targets PI(3)K signaling is rapamycin, which acts to inhibit specific mammalian target of rapamycin (mTOR) complexes, thereby modulating translation in response to survival signals, or nutrient or energy availability. Initially approved as an immunosuppressant, rapamycin and its analogues have antitumor activity in some preclinical models and are currently in clinical trials (4, 27C32). It is therefore important to identify mechanisms of sensitivity and resistance to these agents. We have previously described the effects of aberrant Akt expression on tumorigenesis, chemotherapy responses, and rapamycin sensitivity in the E-lymphoma model (4). Specifically, we have shown that Akt dramatically accelerated mice (C57BL/6 strain) and mice were crossed, and their offsprings were genotyped as described (17, 33). The animals were monitored for development of lymphoma and associated leukemia by biweekly palpation and blood counts, respectively. Upon the appearance of well-palpable lymphomas, the tumors were harvested and either fixed in formalin for histologic evaluation, rendered single-cell suspensions and frozen in 10% DMSO, or transplanted directly into C57Bl/6 mice for treatment studies.