scispace - formally typeset
Search or ask a question
Journal Article•DOI•

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

Naoto Morishita1, Hirokazu Tsukahara1, Kosuke Chayama, Toshiaki Ishida2, Kana Washio1, Takako Miyamura1, Nobuko Yamashita1, Megumi Oda1, Tsuneo Morishima1 •
Okayama University1, Boston Children's Hospital2
15 Jul 2012-Pediatric Blood & Cancer (Pediatr Blood Cancer)-Vol. 59, Iss: 1, pp 83-89
TL;DR: This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P‐Akt) in pediatric B‐pre ALL.
Abstract: Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

Content maybe subject to copyright    Report

氏 名
授 与 し た 学 位
専 攻 分 野 の名 称
学 位 授 与 番 号
学 位 授 与 の 日付
学 位 授 与 の 要 件
学 位 論 文 題 目
森 下 直 人
博 士
医 学
博 甲第 4468 号
平成 24年 3月 2 3 日
医歯薬学総合研究科病態制御科学専攻
(学位 規則 第 4条 第 1項該 当)
ActivationofAktisAssociatedWithPoorPrognosis
and Chemotherapeutic Resistance in Pediatric
B‑PrecursorAcuteLymphoblasticLeukemia
(Akt
の活性化は､小児のB前駆細胞性急性 リンパ性 白血病に
おける予後不良と化学療法抵抗性に関連 している)
論 文 審 査 委 員
教授 谷 本 光音 教授 岩 月 啓 氏 教 授 杉 山 育
学 位 論 文 内 容 の 要 旨
pt3Kl
触 経路壮生存促進性の経路であり､リン酸化によるjkt浄財 ヒは腰痛細胞の成長におい
て重要な役割を果たしている｡しかし､小児
B前納 包性急性リンパ性白血病 (以下､RpreJqL)
の樹散生理におけるjgdの役割はいまだ不明の部分が多Llo今回､我々R 小児BpreAu.にお
けるj
kt活性化が臨床検査学的に分袖 壁学的にどのような意義を有するのか調べた｡
21名の小児 BpreAL患者を対象に行った飽和 勺検討では 骨髄倹体でjgd:が括性化している
患者では菅性化していない患者i3ヒべて化学馳 こ対する反応性が有意に乏しく､生命予後も有
意に悪いことが示 された
CIn trarBfectionによりAktを持続 的に活性化させたBpreA⊥細胞
株 恥 Im6細骨砂 を用いた基砲的検討では､抗脚 Jにより誘導されるアポ トーシスが有意に抑
制されることが示 された｡以上の結果より､
Bpre凡Lにおいて､jgdl措性化樹 臓 超抗性を
もたらす機構
の 1つであり､Jqdが†㈱ こ抵抗性を示 机 ＼児Bpre,qLL患都 こおいて治療標的
になりえることが示唆された｡
論 文 審 査 結 果 の 要 旨
本研究では､′J､児 B･preALLにおいて､骨髄検体で Aktが活性化 している患者 と活性
化が明らかでない患者 との予後を比較 した結果､
Aktの活性化が生存 とかかわっているこ
とを見出 した｡予後に影響を与える機構を解明するため
､B･preALL細胞株であるNalm‑6
株に活性化 した Akt遺伝子をせん孔法で導入 した細胞株に於いては､化学療法剤である
ステロイ ド､オンコビン､ア ドリアマイシン添加によるアポ トーシスが明 らかに抑制 され
ていることを見出 した｡この結果は､A
kt遺伝子の活性化経路がアポ トーシス抑制を介 し
て化学療法治療に対する抵抗性を獲得 していることを示 した新たな知見である｡
よって､本研究者は博士 (医学)の学位を得る資格があると認める｡
Citations
More filters
Journal Article•DOI•
Toward Therapeutic Targeting of Bone Marrow Leukemic Niche Protective Signals in B-Cell Acute Lymphoblastic Leukemia.

[...]

Marjorie C. Delahaye1, Kaoutar-Insaf Salem1, Jeoffrey Pelletier1, Michel Aurrand-Lions1, Stéphane J. C. Mancini1 •
Aix-Marseille University1
08 Jan 2021-Frontiers in Oncology
TL;DR: In this paper, the authors discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment.
Abstract: B-cell acute lymphoblastic leukemia (B-ALL) represents the malignant counterpart of bone marrow (BM) differentiating B cells and occurs most frequently in children. While new combinations of chemotherapeutic agents have dramatically improved the prognosis for young patients, disease outcome remains poor after relapse or in adult patients. This is likely due to heterogeneity of B-ALL response to treatment which relies not only on intrinsic properties of leukemic cells, but also on extrinsic protective cues transmitted by the tumor cell microenvironment. Alternatively, leukemic cells have the capacity to shape their microenvironment towards their needs. Most knowledge on the role of protective niches has emerged from the identification of mesenchymal and endothelial cells controlling hematopoietic stem cell self-renewal or B cell differentiation. In this review, we discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment.

17 citations

Journal Article•DOI•
Clinical utility of miR-143/miR-182 levels in prognosis and risk stratification specificity of BFM-treated childhood acute lymphoblastic leukemia

[...]

Despina Piatopoulou1, Margaritis Avgeris1, Ioanna Drakaki1, Antonios Marmarinos1, Marieta Xagorari1, Margarita Baka2, Apostolos Pourtsidis2, Lydia Kossiva1, Dimitrios Gourgiotis1, Andreas Scorilas1 •
National and Kapodistrian University of Athens1, Boston Children's Hospital2
20 Mar 2018-Annals of Hematology
TL;DR: Bone marrow levels of miR-143/miR-182 were significantly decreased in childhood ALL patients at diagnosis and increased in more than 90% of patients at the EoI, suggesting they could serve as novel prognostic molecular markers for pediatric ALL treated with BFM chemotherapy.
Abstract: Although childhood acute lymphoblastic leukemia (ALL) is characterized by high remission rates, there are still patients who experience poor response to therapy or toxic effects due to intensive treatment. In the present study, we examined the expression profile of miR-143 and miR-182 in childhood ALL and evaluated their clinical significance for patients receiving Berlin–Frankfurt–Munster (BFM) protocol. Bone marrow specimens from 125 childhood ALL patients upon diagnosis and the end-of-induction (EoI; day 33), as well as from 64 healthy control children undergone RNA extraction, polyadenylation, and reverse transcription. Expression levels of miRNAs were quantified by qPCR analysis. Patients’ cytogenetic, immunohistotype and MRD evaluation was performed according to international guidelines. Median follow-up time was 86.0 months (95% CI 74.0–98.0), while patients’ mean DFS and OS intervals were 112.0 months (95% CI 104.2–119.8) and 109.2 months (95% CI 101.2–117.3), respectively. Bone marrow levels of miR-143/miR-182 were significantly decreased in childhood ALL patients at diagnosis and increased in more than 90% of patients at the EoI. Patients’ survival analysis highlighted that children overexpressing miR-143/miR-182 at the EoI presented significantly higher risk for short-term relapse (log-rank test: p = 0.021; Cox regression: HR = 4.911, p = 0.038) and death (log-rank test: p = 0.028; Cox regression: HR = 4.590, p = 0.046). Finally, the evaluation of the miR-143/miR-182 EoI levels along with the established disease prognostic markers resulted to improved prediction of BFM-treated patients’ survival outcome and response to therapy and additionally to superior BFM risk stratification specificity. Concluding, miR-143 and miR-182 could serve as novel prognostic molecular markers for pediatric ALL treated with BFM chemotherapy.

17 citations

Cites background from "Activation of Akt is associated wit..."

  • ...In this regard, the constitutive activation of its primary mediator Akt has been correlated with poor response to apoptosis inducing drugs and inferior survival in pre-B-ALL [18]....

    [...]

Journal Article•DOI•
Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia

[...]

Etan Orgel1, Jessica L. Sea2, Steven D. Mittelman2•
Children's Hospital Los Angeles1, University of California, Los Angeles2
01 Sep 2019-Journal of The National Cancer Institute Monographs
TL;DR: This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connected with obesity, obesity, and adipocytes, and the implications for leukemia therapy.
Abstract: The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy.

16 citations

Journal Article•DOI•
GR-regulating Serine/Threonine Kinases: New Physiologic and Pathologic Implications

[...]

Tomoshige Kino1•
Qatar Airways1
01 Apr 2018-Trends in Endocrinology and Metabolism
TL;DR: Recent progress in research investigating GR phosphorylation by serine/threonine kinases is discussed, along with the possible physiologic and pathophysiologic implications.
Abstract: Glucocorticoid hormones, end products of the hypothalamic–pituitary–adrenal axis, virtually influence all human functions both in a basal homeostatic condition and under stress. The glucocorticoid receptor (GR), a nuclear hormone receptor superfamily protein, mediates these actions of glucocorticoids by acting as a ligand-dependent transcription factor. Because glucocorticoid actions are diverse and strong, many biological pathways adjust them in local tissues by targeting the GR signaling pathway as part of the regulatory loop coordinating complex human functions. Phosphorylation of GR protein by serine/threonine kinases is one of the major regulatory mechanisms for this communication. In this review, recent progress in research investigating GR phosphorylation by these kinases is discussed, along with the possible physiologic and pathophysiologic implications.

15 citations

Journal Article•DOI•
Activity and mechanism of flavokawain A in inhibiting P-glycoprotein expression in paclitaxel resistance of lung cancer.

[...]

Juan Li1, Lei Zheng, Mi Yan1, Jing Wu1, Yongqing Liu1, Xiaona Tian1, Wen Jiang1, Lu Zhang1, Rongmei Wang1 •
Shandong University1
08 Nov 2019-Oncology Letters
TL;DR: FKA is suggested as a potential candidate for the treatment of PTX-resistant lung cancer by blocking the PI3K/Akt pathway.
Abstract: Lung cancer is one of the most common cancers, which is the leading cause of cancer-related death among various cancers worldwide. Flavokawain A (FKA), a chalcone found in the kava plant, exerts potent anticancer activity. However, the activity and mechanisms of FKA in inhibiting the viability of paclitaxel (PTX)-resistant lung cancer A549 (A549/T) have not been investigated. In the present study, the effect of FKA on the viability of A549/T and hepatotoxicity in normal liver epithelial cells was detected by Cell Counting Kit-8 assay. Flow cytometry, western blot analysis and Annexin V-FITC/PI apoptosis detection kit were used to assess cell apoptosis. The effect of FKA on permeability-glycoprotein (P-gp) expression was measured by reverse transcription-PCR and western blot analysis. The results indicated that FKA dose-dependently inhibited cell proliferation and induced cell apoptosis in PTX-resistant A549/T cells, with an IC50 value of ~21 µM, while the IC50 value of A549/T cells to PTX was 34.64 µM. FKA had no hepatic toxicity in liver epithelial cells. P-gp, which contributes to the chemoresistant phenotype, was not expressed in A549 cells but was remarkably enhanced in A549/T cells. FKA (30 µM) decreased P-gp protein expression at 24 h by 3-fold. Furthermore, FKA downregulated P-gp expression by blocking the PI3K/Akt pathway. These findings suggest FKA as a potential candidate for the treatment of PTX-resistant lung cancer.

15 citations

Cites background from "Activation of Akt is associated wit..."

  • ...Increased Akt phosphorylation has been reported to be associated with chemotherapeutic resistance (25)....

    [...]

References
More filters
Journal Article•DOI•
AKT/PKB signaling: navigating downstream.

[...]

Brendan D. Manning1, Lewis C. Cantley2•
Harvard University1, Beth Israel Deaconess Medical Center2
29 Jun 2007-Cell
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.

5,505 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...Akt binds to phosphatidylinositol-3,4,5-triphosphate on the plasma membrane where Akt is activated by phosphorylation at threonine308 (T308) and serine473 (S473) residues....

    [...]

  • ...Antibodies against Akt and PAkt on S473 and HRP-linked secondary antibody were purchased from Cell Signaling Technology Inc. (Irvine, CA) and antibodies against b-actin and Myc tag from Santa Cruz Biotechnology Inc. and Millipore Corp. (Billerica, MA), respectively....

    [...]

  • ...30-Phosphoinositide-dependent kinase 1 phosphorylates the activation loop of Akt at T308, although the mammalian target of rapamycin complex 2 phosphorylates Akt at the hydrophobic motif S473 [7]....

    [...]

Journal Article•DOI•
The activation of Akt/PKB signaling pathway and cell survival

[...]

Gang Song1, Gaoliang Ouyang1, Shideng Bao2, Shideng Bao1•
Xiamen University1, Duke University2
01 Jan 2005-Journal of Cellular and Molecular Medicine
TL;DR: Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival.
Abstract: Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBalpha/Akt1, PKBbeta/Akt2 and PKBgamma/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.

1,811 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...We assume that other pathways aside from P-glycoprotein play an important role in MDR in Nalm-6/Akt, such as expression of another ATP-binding cassette transporter, inhibition of BAD, inhibition of Caspase-9, activation of NF-kB, inhibition of p53, and so forth [6,24]....

    [...]

  • ...Activation of the PI3K/Akt pathway induces activation of nuclear factor-kB and Bcl-2 and inhibition of Bcl-2 antagonist of cell death (BAD), Caspase-9 and p53 [6]....

    [...]

  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

Journal Article•DOI•
P-glycoprotein: from genomics to mechanism

[...]

Suresh V. Ambudkar, Chava Kimchi-Sarfaty, Zuben E. Sauna, Michael M. Gottesman
20 Oct 2003-Oncogene
TL;DR: A model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell is proposed, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported.
Abstract: Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.

985 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...P-glycoprotein is a member of ATP-binding cassette transporters that extract antitumor drugs from cytoplasm and which reduce intracellular drug concentrations to sub-lethal levels [20,21]....

    [...]

  • ...The expression of P-glycoprotein, encoded by the MDR1 gene, is often associated with MDR in tumor cells [20,27]....

    [...]

  • ...In patients with leukemias, lymphomas, and multiple myeloma, P-glycoprotein expression, which is very low at presentation, is occasionally enhanced during administration of long-term chemotherapy or when the disease recurs [20]....

    [...]

Journal Article•DOI•
Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.

[...]

Hans-Guido Wendel1, Elisa de Stanchina1, Jordan S. Fridman2, Jordan S. Fridman1, Abba Malina3, Sagarika Ray1, Scott C. Kogan4, Carlos Cordon-Cardo5, Jerry Pelletier3, Scott W. Lowe1 •
Cold Spring Harbor Laboratory1, Incyte2, McGill University3, University of California, San Francisco4, Memorial Sloan Kettering Cancer Center5
18 Mar 2004-Nature
TL;DR: It is shown that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects.
Abstract: Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

949 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...Furthermore, murine models of Akt activation have shown that constitutively active Akt causes myeloproliferative disease [30], promotes drug resistance, and shortens tumor-free survival [25]....

    [...]

Journal Article•DOI•
The Akt-mTOR tango and its relevance to cancer.

[...]

Nissim Hay1•
University of Illinois at Chicago1
01 Sep 2005-Cancer Cell
TL;DR: Two recent studies used mouse genetics to assess the roles of PTEN and TSC2 in cancer, underscoring the importance of Akt-mTOR interplay for cancer progression and therapy.

767 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

  • ...The PI3K/Akt signaling pathway controls the expression and function of many proteins that are necessary for cell survival, growth, and anti-apoptosis [5]....

    [...]

Related Papers (5)
Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts

[...]

11 Jan 2007-Leukemia
P. L. Tazzari, Alessandra Cappellini, Francesca Ricci, Camilla Evangelisti, Veronica Papa, Tiziana Grafone, Giovanni Martinelli, Roberto Conte, Lucio Cocco, James A. McCubrey, Alberto M. Martelli, Alberto M. Martelli 
Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia

[...]

09 Dec 2013-Cancer Cell
Erich Piovan, Erich Piovan, Jiyang Yu, Valeria Tosello, Daniel Herranz, Alberto Ambesi-Impiombato, Ana Carolina Da Silva, Marta Sanchez-Martin, Arianne Perez-Garcia, Isaura Rigo, Mireia Castillo, Stefano Indraccolo, Justin R. Cross, Elisa de Stanchina, Elisabeth Paietta, Elisabeth Paietta, Janis Racevskis, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Giuseppe Basso, Jules P.P. Meijerink, Carlos Cordon-Cardo, Andrea Califano, Adolfo A. Ferrando 
Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling.

[...]

09 Dec 2003-Proceedings of the National Academy of Sciences of the United States of America
Valerie I. Brown, Junjie Fang, Keith Alcorn, Rosalind Barr, Jenny M. Kim, Robert Wasserman, Stephan A. Grupp 
PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability.

[...]

03 Nov 2008-Journal of Clinical Investigation
Ana Elisa Bauer de Camargo Silva, J. Andrés Yunes, Bruno A. Cardoso, Leila R. Martins, Patrícia Y. Jotta, Miguel Abecasis, Alexandre E. Nowill, Nick R. Leslie, Angelo A. Cardoso, João T. Barata 
Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance

[...]

01 Oct 2006-Cancer Cell
Guo Wei, Guo Wei, David Twomey, David Twomey, Justin Lamb, Krysta D. Schlis, Jyoti Agarwal, Ronald W. Stam, Joseph T. Opferman, Stephen E. Sallan, Monique L. den Boer, Rob Pieters, Todd R. Golub, Scott A. Armstrong