Related Experiment Video
Updated: Sep 11, 2025
14:51
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
3.3K
Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.
Shira G Glushakow-Smith1,2,3,4, Imit Kaur1,4, Simone Sidoli5
1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY.
Biorxiv : the Preprint Server for Biology
|August 12, 2025
Summary
Targeting leukemic stem cells (LSCs) in acute myeloid leukemia (AML) is challenging. A novel combination therapy targeting PI3K and EZH1/2 overcomes resistance, offering a promising treatment strategy for AML patients.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Acquired resistance mechanisms and the inability to target leukemic stem cells (LSCs) contribute to poor outcomes in acute myeloid leukemia (AML).
- Leukemic stem cells (LSCs) are critical drivers of AML pathogenesis and relapse.
Purpose of the Study:
- To investigate the dependencies of LSCs on phosphoinositide 3-kinase (PI3K) signaling.
- To identify resistance mechanisms to PI3K inhibition and develop strategies to overcome them.
Main Methods:
- Isoform-selective PI3K inhibition was employed to assess LSC susceptibility.
- Changes in EZH2/PRC2 complex function and EZH1/2 protein levels were analyzed in response to PI3K inhibition.
- Combination therapy using PI3K and EZH1/2 inhibitors was evaluated in ex vivo and in vivo AML models.
Main Results:
- LSCs demonstrated susceptibility to PI3K targeting, particularly the P110 alpha isoform.
- PI3K inhibition induced dynamic changes in EZH2/PRC2 function, with EZH2 downregulation identified as a resistance mechanism.
- Compensatory upregulation of EZH1 was observed, and its inhibition sensitized AML cells to PI3K inhibition.
- A combination of PI3K and EZH1/2 inhibitors effectively overcame acquired resistance and achieved sustained AML targeting in preclinical models.
Conclusions:
- PI3K inhibition is a viable strategy for targeting LSCs in AML.
- Targeting EZH1/2 in combination with PI3K inhibitors represents a promising therapeutic approach to overcome resistance and improve AML treatment outcomes.
Related Concept Videos
02:56Treatment Resistant Cancers
3.4K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K
01:22PI3K/mTOR/AKT Signaling Pathway
4.0K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
4.0K
02:57Targeted Cancer Therapies
7.8K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.8K
01:20The JAK-STAT Signaling Pathway
9.2K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
9.2K
02:50Combination Therapies and Personalized Medicine
5.1K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.1K