Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression changes upon treatment of T47D breast cancer cells with the Pan-PI3 kinase inhibitor GDC-0941

ABSTRACT: We sought to determine genes whose expression changed upon treatment with a selective inhibitor of class I PI3 kinase. Total of 6 samples: cells were treated with GDC-0941 at a concentration of 1mM for 6 hours (3 replicates) and control (3 replicates)

ORGANISM(S): Homo sapiens

SUBMITTER: Mark Lackner

PROVIDER: E-GEOD-20719 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.

O'Brien Carol C Wallin Jeffrey J JJ Sampath Deepak D GuhaThakurta Debraj D Savage Heidi H Punnoose Elizabeth A EA Guan Jane J Berry Leanne L Prior Wei Wei WW Amler Lukas C LC Belvin Marcia M Friedman Lori S LS Lackner Mark R MR

Clinical cancer research : an official journal of the American Association for Cancer Research 20100507 14

<h4>Purpose</h4>The class I phosphatidylinositol 3' kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC-0941.<h4>Experimental design</h4>We used a large panel of breast cancer ...[more]

PMID: 20453058

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Project description:Somatic NOTCH1 mutations are found in ~60% of T lineage acute lymphoblastic leukemias (T-ALLs). Notch1 is cleaved by γ secretase to generate activated Notch intracellular domain (NICD) proteins. The NOTCH1 mutations found in T-ALL constitutively activate Notch1 signaling by increasing NICD levels. Genetic alterations in components of the Ras/PI3 kinase (PI3K)/Akt pathway are also highly prevalent in T-ALL, and often coexist with NOTCH1 mutations. Exposing a T-ALL cell line to the PI3 kinase (PI3K) inhibitor GDC-0941 generated drug resistant clones that down-regulated NICD expression. To address the in vivo relevance of this unexpected observation, we transplanted primary wild-type (WT) and KrasG12D mutant T-ALLs into recipient mice, and treated them with GDC-0941 alone and in combination with the MEK inhibitor PD0325901 (PD901). Although many leukemias responded dramatically to these targeted agents in vivo, drug-resistant clones invariably emerged. Multiple resistant T-ALLs lost NICD expression through mechanisms that included loss of Notch1 mutations found in the parental T-ALL. These GDC-0941-resistant leukemias exhibited reduced expression of many Notch1 target genes, elevated levels of phosphorylated Akt (pAkt), and displayed cross-resistance to γ secretase inhibitors (GSIs). Consistent with these data, inhibiting Notch1 activity in T-ALL cells enhanced PI3K signaling, providing a likely mechanism for in vivo selection against clones with Notch1 pathway activation. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly “switch” to become deleterious during treatment with a PI3K inhibitor. These data advance our understanding of T-ALL pathogenesis and have implications for implementing new therapeutic regimens. We analyzed 28 mouse T-ALL samples obtained after in vivo treatment with GDC-0941 alone or GDC-0941 + PD0325901. These T-ALL samples are either Kras wild type or harbor a KrasG12D mutations.

Dataset Information

Gene expression changes upon treatment of T47D breast cancer cells with the Pan-PI3 kinase inhibitor GDC-0941

Publications

Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.

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