mTOR inhibition enhances efficacy of dasatinib in ABL -rearranged Ph-like B-ALL

Oncotarget
Moran GotesmanDavid A Fruman

Abstract

High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) include Philadelphia chromosome-positive (Ph+) B-ALL driven by the BCR-ABL1 oncogene and a more recently identified subtype known as BCR-ABL-like or Ph-like B-ALL. A hallmark of both Ph+ and Ph-like B-ALL is constitutive activation of tyrosine kinase signaling that is potentially targetable with tyrosine kinase inhibitors (TKIs). B-ALL cells also receive extracellular signals from the microenvironment that can maintain proliferation and survival following treatment with TKIs. Therefore, there is strong rationale for combining TKIs with other therapies targeting signal transduction pathways. Here we show that combinations of the ABL-directed TKI dasatinib with mTOR kinase inhibitors (TOR-KIs) are more effective than TKI alone against patient-derived Ph-like B-ALL cells harboring rearrangements of ABL1 or ABL2. We also report the establishment of a new human Ph-like B-ALL cell line that is stromal cell-independent in vitro and can be used for xenograft experiments in vivo. These findings provide rationale for clinical testing of TKI plus TOR-KIs in children and adults with Ph-like B-ALL and a new experimental tool to test promising therapeutic strategies in this po...Continue Reading

References

Jan 15, 2010·Nature Medicine·Matthew R JanesDavid A Fruman
Sep 10, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Collin Vu, David A Fruman
Mar 19, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jessica K AltmanLeonidas C Platanias
Sep 11, 2014·The New England Journal of Medicine·Kathryn G RobertsCharles G Mullighan
Mar 26, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bristi BasuUdai Banerji
Nov 22, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kathryn G RobertsCharles G Mullighan
Dec 7, 2016·Blood·Nitin JainMarina Konopleva
Aug 13, 2017·Cell·David A FrumanRobert T Abraham

❮ Previous
Next ❯

Citations

Feb 24, 2019·Cells·Carolina SimioniLuca M Neri
Apr 3, 2020·International Journal of Molecular Sciences·Parveen ShirazLori Muffly
Mar 20, 2020·The Journal of Clinical Investigation·Christian HurtzSarah K Tasian
Jul 3, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yang-Yang DingKai Tan
Nov 6, 2021·Scientific Reports·Thanh-Trang VoDavid A Fruman

❮ Previous
Next ❯

Datasets Mentioned

BETA
AALL1131

Methods Mentioned

BETA
xenograft
flow cytometry
FACS

Clinical Trials Mentioned

NCT01406756
NCT02723994
NCT02484430

Software Mentioned

GraphPad
FlowJo
Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.