Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Why Tumors Become Drug-Resistant

Published: Monday, August 12, 2013
Last Updated: Monday, August 12, 2013
Bookmark and Share
New findings could lead to drugs that fight back when tumors don’t respond to treatment.

Cancer drugs known as ErbB inhibitors have shown great success in treating many patients with lung, breast, colon and other types of cancer. However, ErbB drug resistance means that many other patients do not respond, and even among those who do, tumors commonly come back.

A new study from MIT reveals that much of this resistance develops because a protein called AXL helps cancer cells to circumvent the effects of ErbB inhibitors, allowing them to grow unchecked. The findings suggest that combining drugs that target AXL and ErbB receptors could offer a better way to fight tumors, says Doug Lauffenburger, the Ford Professor of Bioengineering, head of MIT’s Department of Biological Engineering and an affiliate member of MIT’s Koch Institute for Integrative Cancer Research.

“Drug resistance is the major challenge in cancer these days. People are coming up with a lot of targeted therapies for particular genes and identifying drugs that work against them, but resistance is just invariably the issue,” says Lauffenburger, the senior author of a paper describing the findings in the Aug. 6 issue of Science Signaling.

ErbBs, a family of epithelial growth factor receptors (EGFRs), are proteins that are often overactive in cancer cells, causing them to grow and divide uncontrollably. The drug Iressa is used to treat lung cancer patients whose tumors overexpress one type of ErbB mutant, and Herceptin targets another ErbB family member that is found in certain types of breast cancer.

“There are a lot of excellent drugs that target EGFR itself or other members of that family, yet they have these limitations,” Lauffenburger says.

Systems analysis

In the new study, Lauffenburger and colleagues set out to identify factors that help tumor cells become resistant to EGFR and other ErbB inhibitors. To do this, they developed a new computer model and applied it to a large dataset called the Cancer Cell Line Encyclopedia, which includes information on about 1,000 human cancer lines and their responses to different drugs.

Led by biological engineering graduate student Aaron Meyer, lead author of the paper, the researchers created a machine learning program that can sift through the data and look for pairs of overexpressed proteins that make tumor cells resistant to EGFR inhibitors. In this case, they searched for the EGFR protein in combination with every other possible protein in the database, one pair at a time.

Through this analysis, the researchers found that EGFR paired with the AXL receptor appears to be the strongest marker for EGFR inhibitor resistance. They found this pattern across many types of cancer, including lung, breast and pancreatic.

A few previous studies have shown that overexpression of AXL is associated with resistance to EGFR inhibitors in a particular tumor, but this is the first systematic study to demonstrate the correlation, Lauffenburger says. This “systems biology” approach, which focuses on complex interactions within biological systems, is critical for finding new drugs that work together to knock out cancer’s defense mechanisms, he says.

“It’s now well known that when you look for a single pathway, you won’t get to an effective therapeutic. You will end up with resistance,” Lauffenburger says. “You’ve got to look at pathways in combination, you’ve got to look at whole interacting networks. That’s the only way.”

Clues to a mystery

Then, in experiments on cancer cells grown in the lab, the researchers found that the AXL protein tends to cluster with EGFR on cell surfaces, so when EGFR is activated, AXL also becomes active. AXL then not only stimulates further much of the same cellular machinery targeted by EGFR, but also additional pathways provoking cell growth and division. AXL also helps cells become more motile, allowing cancer to spread through the body.

The researchers also showed that other members of the ErbB family beyond EGFR similarly cluster with AXL. This suggests that AXL inhibition may also be effective for treating breast cancers dependent on ErbB2 or ovarian cancers that overexpress ErbB3, Lauffenburger says.

The study sheds light on the complicated interactions between EGFR and other proteins that help tumors re-emerge after initial treatment with EGFR inhibitors, and could help researchers develop improved treatments, says Trever Bivona, an assistant professor of medicine at the University of California at San Francisco.

“The implication that emerges from the findings is that the way receptor kinases interact to undermine sensitivity to treatment is quite complex,” says Bivona, who was not part of the research team.

High levels of AXL have previously been found in triple-negative breast cancer cells, which lack the three most common breast cancer markers — estrogen receptors, progesterone receptors and HER2 receptors. The new finding may explain why EGFR inhibitors fail to work on these tumors even though they have high EGFR levels, Lauffenburger says.

“Triple-negative breast cancer cells were a special interest of ours mainly because it’s always been such a mystery why they have not responded to EGFR inhibitors,” he says.

The new study suggests that AXL inhibitors, either alone or in combination with EGFR inhibitors, might be an effective treatment for triple-negative breast cancer, which is now treated with chemotherapy drugs that have severe side effects. A handful of clinical trials are currently testing AXL inhibitors against different types of cancer, and Lauffenburger is now planning studies in mice to investigate the effects of combining AXL and EGFR pathway inhibitors.

Biological engineering graduate student Miles Miller and Frank Gertler, a professor of biology and member of the Koch Institute, are also co-authors of the paper. The research was funded by the National Cancer Institute Integrative Cancer Biology Program, the Department of Defense Breast Cancer Research Program, and the Koch Institute Frontier Research Program.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,400+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

A Programming Language for Living Cells
New language lets researchers design novel biological circuits.
Monday, April 04, 2016
Cancer Cells Remodel Environments Before Spreading
Researchers at MIT have found that the cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Wednesday, March 16, 2016
Paving the Way for Metastasis
Cancer cells remodel their environment to make it easier to reach nearby blood vessels.
Tuesday, March 15, 2016
A New Way to Discover DNA Modifications
Researchers systematically find molecules that help regulate and protect DNA.
Wednesday, March 02, 2016
Mapping Regulatory Elements
Systematically searching DNA for regulatory elements indicates limits of previous thinking
Wednesday, February 03, 2016
Curing Disease by Repairing Faulty Genes
New delivery method boosts efficiency of CRISPR genome-editing system.
Wednesday, February 03, 2016
Supply Chain
Chemists discover how a single enzyme maintains a cell’s pool of DNA building blocks.
Wednesday, January 13, 2016
How Cancer Cells Spread
Study offers new targets for drugs that may prevent cancer from spreading.
Thursday, December 17, 2015
Scaling Up Synthetic-Biology Innovation
MIT professor’s startup makes synthesizing genes many times more cost effective.
Monday, December 14, 2015
Delivering microRNAs for Cancer Treatment
Scientists exploit gene therapy to shrink tumors in mice with an aggressive form of breast cancer.
Wednesday, December 09, 2015
CRISPR-Cas9 Genome Editing Hurdle Overcome
Team re-engineers system to dramatically cut down on editing errors; improvements advance future human applications.
Thursday, December 03, 2015
Drug-Resistance Mechanism in Tumor Cells Unravelled
Targeting the RNA-binding protein that promotes resistance could lead to better cancer therapies.
Friday, October 23, 2015
Quantum Physics Meets Genetic Engineering
Researchers use engineered viruses to provide quantum-based enhancement of energy transport.
Friday, October 16, 2015
Viruses Join Fight Against Harmful Bacteria
Engineered viruses could combat human disease and improve food safety.
Friday, September 25, 2015
Targeting DNA
Protein-based sensor could detect viral infection or kill cancer cells.
Tuesday, September 22, 2015
Scientific News
Cell Transplant Treats Parkinson’s in Mice
A University of Wisconsin—Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell.
Understanding Female HIV Transmission
Glowing virus maps points of entry through entire female reproductive tract for first time.
Genetic Markers Influence Addiction
Differences in vulnerability to cocaine addiction and relapse linked to both inherited traits and epigenetics, U-M researchers find.
A lncRNA Regulates Repair of DNA Breaks in Breast Cancer Cells
Findings give "new insight" into biology of tough-to-treat breast cancer.
Detection of HPV in First-Void Urine
Similar sensitivity of HPV test on first void urine sample compared to cervical smear.
Shape Of Tumor May Affect Whether Cells Can Metastasize
Illinois researchers found that the shape of a tumor may play a role in how cancer cells become primed to spread.
Computational Model Finds New Protein-Protein Interactions
Researchers at University of Pittsburgh have discovered 500 new protein-protein interactions (PPIs) associated with genes linked to schizophrenia.
MicroRNA Pathway Could Lead to New Avenues for Leukemia Treatment
Cancer researchers at the University of Cincinnati have found a particular signaling route in microRNA (miR-22) that could lead to targets for acute myeloid leukemia, the most common type of fast-growing cancer of the blood and bone marrow.
Analysis of Dog Genome will Provide Insight into Human Disease
An important model in studying human disease, the non-coding RNA of the canine genome is an essential starting point for evolutionary and biomedical studies – according to a new study led by The Genome Analysis Centre (TGAC).
New Insights into Gene Regulation
Researchers have solved the three-dimensional structure of a gene repression complex that is known to play a role in cancer.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,400+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!