Protein Mapping Improves Understanding of Cancer Cells

Researchers recently created a map of vast interactions between proteins in lung cancer to better understand drug-resistant disease, according to a study published by Nature Communication.

The mapping method showed novel ways to target cells that cause genetic mutations, using an approved drug to target a commonly mutated gene in lung cancer cells.

A majority of the genes that drive cancer are not able to be targeted with drugs, and investigators are uncertain about how to use tumor suppressor genes in their favor. With tumor suppressors eliminated, cancer cells become unstable, but then the target is removed, according to the study.

"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," said senior author Haian Fu, PhD. "In this way, changes in a tumor suppressor may be linked with the response of the target to the connected drug."

Investigators have long been searching for ways to target STK11/LKB1 mutations, which are present in up to 25% cases of non-small cell lung cancers. The tumor suppressor gene encodes an enzyme that is believed to control cell migration and metabolism, according to the study.

Understanding how various aspects of a cell fit together can at times be complicated and time consuming before valuable information is discovered. The authors said that Förster resonance energy transfer (FRET) is not nearly as complex, and it was used to create the gene map in the study. If 2 fluorescent similarly colored molecules are within 10 nanometers from each other, they can be detected by FRET, according to the study.

The authors created a platform that enabled them to tag proteins with florescent molecules that were then introduced to cancer cells. This process allowed the study authors to detect interaction between cells and map their associations.

The team started with 83 proteins associated with lung cancer, and discovered 260 previously unknown interactions, according to the study. All interactions were tested multiple times, in different manners and cell lines to verify the interactions.

The authors focused on the Myc oncoprotein, which is considered undruggable, according to the study. However, through the map, the investigators found that the protein was linked to the protein Brd4, for which there is an inhibitor, according to the study. The authors believe that the newly discovered Brd-NSD3-Myc pathway could target lung cancer cells and improve outcomes.

One of the aspects of the map suggests that the breast cancer drug palbociclib may also be effective against LKB1-mutated cells by inhibiting CDK4. This was confirmed through a genomic data analysis and cell culture experiments.

The study authors discovered that cancer cells with LKB1 were highly sensitive to palbociclib. This reaction may show promise as a biomarker for the efficacy of the drug, according to the study.

Through this mapping technique, researchers were able to gain a better understanding about the protein interaction between lung cancer cells, which may lead to more targeted and effective treatments.