Related Experiment Video
Updated: Oct 29, 2025
13:34
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
10.4K
Cell Line-Specific Network Models of ER+ Breast Cancer Identify Potential PI3Kα Inhibitor Resistance Mechanisms and
Jorge Gómez Tejeda Zañudo1,2, Pingping Mao2, Clara Alcon3
1Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. jgtz@broadinsitute.org jmontero@ibecbarcelona.eu rza1@psu.edu nikhil_wagle@dfci.harvard.edu.
Cancer Research
|July 14, 2021
Summary
Network models identified effective drug combinations for PI3Kα-mutant breast cancer, revealing FOXO3 downregulation as a resistance mechanism. This approach aids in overcoming cancer drug resistance.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Targeted therapies like alpelisib are crucial for invasive solid tumors, but therapeutic resistance remains a significant challenge.
- Estrogen receptor-positive (ER+), PIK3CA-mutant breast cancer often develops resistance to PI3Kα inhibitors.
- Identifying novel resistance mechanisms and effective drug combinations is essential for durable tumor control.
Purpose of the Study:
- To utilize a network-based mathematical model to identify drug combinations and sensitivity regulators for alpelisib in ER+ PIK3CA-mutant breast cancer.
- To experimentally validate model predictions regarding alpelisib efficacy and resistance mechanisms.
- To develop cell line-specific network models for predicting differential drug responses.
Main Methods:
- Development and application of a network-based mathematical model to analyze PI3Kα signaling pathways.
- Experimental validation of predicted drug combinations (alpelisib with BH3 mimetics) in ER+ breast cancer cell lines.
- Investigation of FOXO3 downregulation as a potential resistance mechanism and analysis of BCL2 family member expression.
Main Results:
- The model accurately predicted the combination of alpelisib with BH3 mimetics (e.g., MCL1 inhibitors) as efficacious.
- FOXO3 downregulation was identified as a novel mechanism reducing sensitivity to alpelisib.
- Cell line-specific sensitivity to alpelisib and BH3 mimetic combinations correlated with BCL2 family member expression.
Conclusions:
- Network-based mathematical models are valuable tools for identifying cancer drug resistance mechanisms and predicting effective therapeutic strategies.
- The study highlights the potential of combining alpelisib with BH3 mimetics for ER+ PIK3CA-mutant breast cancer.
- Understanding oncogenic signaling networks and validating model predictions experimentally can overcome challenges in targeted cancer therapy.
More Related Videos
07:45Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
6.4K
08:48An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
8.4K
Related Concept Videos
02:57Targeted Cancer Therapies
8.0K
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...
8.0K
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
02:26Protein Networks
4.2K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.2K
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
01:22PI3K/mTOR/AKT Signaling Pathway
4.3K
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...
4.3K
02:34Inhibition of Cdk Activity
5.1K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.1K