Related Experiment Video
Updated: Nov 1, 2025
14:51
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
3.4K
Stepwise evolution of therapy resistance in AML
Philippe Gui1, Trever G Bivona1
1Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Cancer Cell
|June 25, 2021
Summary
Relapse in acute myeloid leukemia (AML) patients treated with FLT3 inhibitors (FLT3i) involves residual cancer cells surviving and expanding. This study reveals how microenvironment factors drive early resistance, which progresses to mutation-driven late resistance to gilteritinib.
Area of Science:
- Hematology
- Oncology
- Cancer Biology
Background:
- Relapse in acute myeloid leukemia (AML) is a significant challenge, often driven by treatment resistance.
- FLT3 inhibitors (FLT3i) are crucial in AML therapy, but resistance remains a major hurdle.
- Understanding the mechanisms of resistance is vital for improving patient outcomes.
Purpose of the Study:
- To investigate the stepwise evolution of resistance to gilteritinib, a FLT3 inhibitor, in AML.
- To differentiate between early microenvironment-driven resistance and late mutation-driven resistance.
- To elucidate the mechanisms underlying treatment failure in FLT3-mutated AML.
Main Methods:
- Utilized a multifaceted approach combining in vitro and in vivo models.
- Employed techniques to analyze cellular responses and genetic alterations.
- Characterized the role of the tumor microenvironment in resistance development.
Main Results:
- Demonstrated that early resistance to gilteritinib is influenced by the tumor microenvironment.
- Showed a transition from microenvironment-dependent resistance to acquired mutations driving late-stage resistance.
- Identified specific pathways and cellular interactions contributing to gilteritinib resistance.
Conclusions:
- Resistance to FLT3 inhibitors in AML is a dynamic, stepwise process.
- The tumor microenvironment plays a critical role in the initial stages of resistance.
- Acquired mutations are key drivers of late-stage, persistent resistance to gilteritinib, necessitating further therapeutic strategies.
Related Concept Videos
02:56Treatment Resistant Cancers
3.5K
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...
3.5K
02:07Tumor Progression
6.7K
Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
6.7K
02:50Combination Therapies and Personalized Medicine
5.3K
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...
5.3K
01:15Differentiation of Common Myeloid Progenitor Cells
3.6K
Common myeloid progenitors (CMPs) are oligopotent cells that can differentiate into granulocytes and macrophages. Granulocytes and macrophages are essential for protecting the body against bacterial, viral, or fungal infections. They migrate from the bone marrow into the circulating blood to reach specific tissue sites where they differentiate and help in immune surveillance. However, they survive only for a few days and must be continuously made available to the organism to maintain a robust...
3.6K
01:28Drug Therapy
131
The advent of drug therapy has profoundly shaped modern mental health care, providing targeted treatments for a range of psychological disorders. Psychotherapeutic drugs, classified into antianxiety, antidepressant, and antipsychotic medications, address symptoms across anxiety disorders, mood disorders, and schizophrenia. While these medications have transformed patient outcomes, they require careful management due to their potential side effects and limitations.
Antianxiety Medications
Antianxiety Medications
131