Spider web of cancer proteins reveals new drug possibilities

February 16, 2017 by Quinn Eastman
Credit: Emory University

Scientists at Winship Cancer Institute of Emory University have mapped a vast spider web of interactions between proteins in lung cancer cells, as part of an effort to reach what was considered "undruggable."

This approach revealed new ways to target cells carrying mutations in cancer-causing genes. As an example, researchers showed sensitivity to an FDA-approved drug, palbociclib, for a gene that is commonly mutated in lung , which is now being tested in a clinical study.

The results are published online in Nature Communications.

Many genes that drive the growth of cancer cells don't have any drugs available against them. For "tumor suppressor" genes, researchers are often not sure how to go after them. When the tumor suppressors are gone, cells often become more deranged, but there's no bullseye left to target. Exploiting the cancer cells' derangement remains a daunting challenge, says senior author Haian Fu, PhD.

"Our approach is to place tumor suppressors in the context of a network of cancer-associated proteins and link tumor suppressors to drugs through a known drug target protein," Fu says. "In this way, changes in a tumor suppressor may be linked with the response of the target to the connected drug."

The study is part of a push by the National Cancer Institute's Cancer Target Discovery and Development (CTD2) network to translate genomics data into therapeutic strategies, he says. Emory is a member of the NCI CTD2 network.

Fu holds the Winship Partner in Research endowed chair and is leader of Winship's Discovery and Developmental Therapeutics Program, director of the Emory Chemical Biology Discovery Center and professor of pharmacology and hematology and medical oncology. Co-corresponding author Fadlo Khuri, MD, maintains his professor appointment at Winship Cancer Institute and is now president of the American University of Beirut in Lebanon.

Cancer researchers have been searching for ways to target mutations in the gene STK11/LKB1, found in 15 to 25 percent of non-small cell lung cancers. The STK11/LKB11 encodes an enzyme that is thought to regulate cell migration and metabolism.

One of the Winship team's newly identified interactions—a "thread" in the spider web—suggested that palbociclib, recently approved against metastatic breast cancer, may work against cells carrying mutations in LKB1, through LKB1's connection to CDK4, the target of palbociclib.

That prediction was supported by genomic data analysis and cell culture experiments: with LKB1 defects showed a tendency of increased sensitivity to palbociclib. Now a study led by Taofeek Owonikoko, MD, at Winship is using LKB1 status as a biomarker for interpreting the effect of palbociclib.

How OncoPPI works

If cells are complex machines, then a number of ways exist for figuring out how the machines' parts, dominated by proteins, fit together. Some of them involve multiple washing steps to remove nonspecific partners after breaking cells apart, but FRET (Förster resonance energy transfer) does not. If two fluorescent molecules with colors that are near on the spectrum are close enough (less than 10 nanometers), that proximity can be detected by FRET.

Fu and his colleagues established a large-scale platform for tagging proteins with two different fluorescent molecules, introducing them into cancer cells, and then detecting interactions between the proteins. They call this network of cancer-associated proteins "OncoPPI."

Starting with a set of 83 lung cancer-related proteins, the team detected more than 260 interactions that were not known previously. They tested the interactions several times, in different orientations, and in other cell lines with selected interactions to establish reliability. More than 80 percent of the interactions the researchers detected could be confirmed by another method (GST pulldown).

As an additional example to illustrate the utility of a protein interaction web, the team focused on the prominent oncoprotein Myc, which was also considered "undruggable." But the researchers could connect Myc indirectly through NSD3 to another protein called Brd4, against which inhibitors have been developed. Brd4 inhibitors are being currently tested in clinical trials. This finding revealed a new pathway Brd4-NSD3-Myc as potential targets for therapeutic intervention, Fu says.

Explore further: Researchers find supposed tumor-suppressing protein actually promotes cancer

Related Stories

Researchers find supposed tumor-suppressing protein actually promotes cancer

January 24, 2017
Tulane University researchers have discovered that the protein PHLDB3, thought to be a potential tumor suppressor, actually allows cancer cells to thrive in pancreatic, prostate, colon, breast, lung, and other common cancers. ...

Researchers discover molecular approach to promote cancer cell death

May 21, 2015
Lung cancer researchers at Winship Cancer Institute of Emory University have discovered a novel strategy to exploit apoptosis, a form of programmed cell death, for the treatment of lung cancer. The protein Bcl-2 is a known ...

Study finds new drug target for metastatic breast cancer

April 11, 2013
Research led by Dr. Suresh Alahari, Professor of Biochemistry and Molecular Biology at LSU Health Sciences Center New Orleans, is the first to report that two specific tumor suppressor genes work in concert to inhibit the ...

Anti-tumor immunity identified with new ovarian cancer treatment strategy

September 13, 2016
Few effective treatments have been approved to treat ovarian cancer, the deadliest of all cancers affecting the female reproductive system. Now, new research from The Wistar Institute demonstrates how a drug already in clinical ...

Researchers ID cancer gene-drug combinations ripe for precision medicine

July 21, 2016
In an effort to expand the number of cancer gene mutations that can be specifically targeted with personalized therapies, researchers at University of California San Diego School of Medicine and Moores Cancer Center looked ...

The silencer: Study reveals how a cancer gene promotes tumor growth

June 23, 2016
A Yale-led study describes how a known cancer gene, EGFR, silences genes that typically suppress tumors. The finding, published in Cell Reports, may lead to the development of more effective, individualized treatment for ...

Recommended for you

Promising new treatment for rare pregnancy cancer leads to remission in patients

November 24, 2017
An immunotherapy drug can be used to cure women of a rare type of cancer arising from pregnancy when existing treatments have failed.

Researchers unravel novel mechanism by which tumors grow resistant to radiotherapy

November 23, 2017
A Ludwig Cancer Research study has uncovered a key mechanism by which tumors develop resistance to radiation therapy and shown how such resistance might be overcome with drugs that are currently under development. The discovery ...

African Americans face highest risk for multiple myeloma yet underrepresented in research

November 23, 2017
Though African-American men are three times more likely to be diagnosed with multiple myeloma, a type of blood cancer, most scientific research on the disease has been based on people of European descent, according to a study ...

Encouraging oxygen's assault on iron may offer new way to kill lung cancer cells

November 22, 2017
Blocking the action of a key protein frees oxygen to damage iron-dependent proteins in lung and breast cancer cells, slowing their growth and making them easier to kill. This is the implication of a study led by researchers ...

One-size treatment for blood cancer probably doesn't fit all, researchers say

November 22, 2017
Though African-American men are three times more likely to be diagnosed with a blood cancer called multiple myeloma, most scientific research on the disease has been based on people of European descent, according to a study ...

One in four U.S. seniors with cancer has had it before

November 22, 2017
(HealthDay)—For a quarter of American seniors, a cancer diagnosis signals the return of an old foe, new research shows.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.