ArticleNature2014
Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 70 citations in OpenAlex.
- Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.The Journal of experimental medicine · 2025Article
- Glucocorticoid Therapy in Acute Lymphoblastic Leukemia: Navigating Short-Term and Long-Term Effects and Optimal Regimen Selection.Current hematologic malignancy reports · 2024Review
- Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL.Blood advances · 2023Article
- Notch1 promotes resistance to cisplatin by up-regulating Ecto-5'-nucleotidase (CD73) in triple-negative breast cancer cells.Cell death discovery · 2023Article
- Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia-The State-of-the-Art Knowledge and Future Prospects.International journal of molecular sciences · 2022Review
- A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC).Clinical breast cancer · 2022Article
- Article
- Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures.Nature communications · 2021Article
- Article
- A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia.BMC pharmacology & toxicology · 2020Article
- Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia.Leukemia · 2020Article
- The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia.Cold Spring Harbor perspectives in medicine · 2020Review
- HSF1-Mediated Control of Cellular Energy Metabolism and mTORC1 Activation Drive Acute T-Cell Lymphoblastic Leukemia Progression.Molecular cancer research : MCR · 2020Article
- Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias.PLoS genetics · 2019Article
- High-Complexity shRNA Libraries and PI3 Kinase Inhibition in Cancer: High-Fidelity Synthetic Lethality Predictions.Cell reports · 2019Article
- Integrative analysis of h-prune as a potential therapeutic target for hepatocellular carcinoma.EBioMedicine · 2019Article
- Overexpression of CD59 inhibits apoptosis of T-acute lymphoblastic leukemia via AKT/Notch1 signaling pathway.Cancer cell international · 2019Article
- NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras.Cold Spring Harbor perspectives in medicine · 2018Review
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
Abstract
Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.