Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance

Wei, Guo; Twomey, David; Lamb, Justin; Schlis, Krysta; Agarwal, Jyoti; Stam, Ronald W.; Opferman, Joseph T.; Sallan, Stephen E.; Boer, Monique L. den; Pieters, Rob; Golub, Todd R.; Armstrong, Scott A.

doi:10.1016/j.ccr.2006.09.006

Cited by 484 publications

(465 citation statements)

References 61 publications

Supporting

Mentioning

435

Contrasting

Unclassified

Order By: Relevance

“…In contrast to MLLrearranged infant ALL, high-level S100A8/S100A9 expression appeared largely absent in other types of childhood ALL (Figure 1b), suggesting that the inhibition of MCL1 in prednisolone resistant non-infant pediatric precursor B-ALL cells may be far more effective. 9,10 Furthermore, we show that high-level expression of S100A8 and S100A9 is not only associated with in vitro prednisolone resistance, but also correlates (although not significantly) with poor in vivo prednisone responses. Interestingly, the level of S100A8/A9 expression appeared a stronger predictor of a poor clinical outcome than the in vivo prednisone response.…”

Section: Discussionmentioning

confidence: 69%

“…9 However, modulation of MCL1 in prednisolone-resistant MLL-rearranged cell line models only resulted in moderate sensitization, 9,10 implying that other and more relevant resistance mechanisms are involved. In our earlier efforts to define a prednisolone-resistance-associated gene expression profile, the obtained gene signature was compromised by a relatively low accuracy, presumably due to small numbers of patient samples.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

View full text Add to dashboard Cite

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca 2 þ fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca 2 þ and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca 2 þ levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca 2 þ fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.Leukemia ( Keywords: prednisolone resistance; S100A8 and S100A9; calcium signaling; MLL-rearranged infant leukemia INTRODUCTIONSince the early 1960s, treatment results for childhood acute lymphoblastic leukemia (ALL) began to improve steadily and continued to progress ever since. Consequently, the survival chances for childhood ALL, in general, nowadays exceed 85%. 1 Unfortunately, this tremendous step forward has not been equally beneficial for all patients. This is especially true for infants (o1 year of age) with ALL carrying leukemia-specific chromosomal translocations involving the MLL gene, which occur in B80% of the infant ALL cases. 2,3 Depending on the treatment protocol, survival chances for MLL-rearranged infant ALL patients are at best B40%. 3 Considerably contributing to this poor outcome is cellular resistance to multiple chemotherapeutic drugs, in particular to glucocorticoids like prednisone and dexamethasone, which form the cornerstone of childhood ALL treatment regimes. Prednisolone (the biologically active metabolite of prednisone) dosages needed to eliminate 50% of infant ALL cells in vitro typically are B500 --fold higher than the dosages required to eradicate similar amounts of precursor B-ALL cells from children older than one year of age (that is, non-infants). 4 Moreover, approximately 30% of infants with MLL-rearranged ALL show a poor prednisone response in vivo, compared with only B10% of non-infant pediatric precursor B-ALL cases. 5 As the in vitro prednisolone response and the prednisone response in vivo represent important prognostic factors, 6 --8 ...

show abstract

Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Finally, several lines of evidence are in support of Mcl-1 regulation at the translational level. Studies have suggested that, in other contexts, Mcl-1 is a potential downstream target of eIF4E (Wei et al, 2006;Wendel et al, 2007;Mills et al, 2008). Recently Wei et al (2006) described the ability of rapamycin (mTOR inhibitor) to induce Mcl-1 but not Bcl-2 or Bcl-XL block in protein translation.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have suggested that, in other contexts, Mcl-1 is a potential downstream target of eIF4E (Wei et al, 2006;Wendel et al, 2007;Mills et al, 2008). Recently Wei et al (2006) described the ability of rapamycin (mTOR inhibitor) to induce Mcl-1 but not Bcl-2 or Bcl-XL block in protein translation. Moreover, mir-29b (microRNAs are acting as endogenous sequence that specifically suppress translation) was recently reported to regulate Mcl-1 expression, and its enforced expression made cancer cells sensitive to TRAIL (Mott et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

et al. 2009

View full text Add to dashboard Cite

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

show abstract

“…Our group, and others, have demonstrated that rapalogs have an additive or synergistic effect when combined with many agents in vitro, including methotrexate, corticosteroids, doxorubicin, etoposide, and asparaginase. [136,[144][145][146] An added benefit was not found when rapalogs were combined with vincristine in vitro; however, the combination was found to be more effective than either drug alone in vivo. [136,139,146] Rapalogs have been studied in vivo in combination with methotrexate and corticosteroids.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

View full text Add to dashboard Cite

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

show abstract

Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance

Cited by 484 publications

References 61 publications

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Contact Info

Product

Resources

About