Emory researchers have discovered widespread distortions of a cell protein interaction equipment resulting from cancer-causing mutations. They developed a ground-penetrating radar, which is used to map the hidden landscape of anticancer medication opportunities.
InCell, the results are revealed.
The evolution of protein-protein interactions is the result of a change in protein formation, according to a leading author. A mutation may form a new epitope, forming a new interaction surface. Such a single protein residue alteration can rewire the cell, leading it down the path of an oncogenic program.
Assistant professor Xiulei Mo, PhD, instructor Qiankun Niu, PhD, and assistant professor Andrey Ivanov, PhD, are among the co-first authors of the Cell paper.
These new mutation-enhanced protein-protein interactions neoPPIs were identified in cancer, revealing potential tumor-selective drugs.
Researchers investigate how a common mutation in the gene BRAF V600E, found in most melanomas, as well as lung and colon cancers triggers a new connection between the BRAF-encoded protein and a redox regulator protein KEAP1 have been investigated. However, this relationship has not been previously described.
Cancer cells produce more of the redox enzyme NQO1. This provides an opportunity to poison the cells by feeding them a compound that becomes toxic. Taking advantage of this vulnerability, researchers found that BRAF-mutated cells were more sensitive to the compound DNQ (deoxynyboquinone).
There were already targeted therapies that targeted the BRAF V600E mutation, such as vemurafenib, which was FDA-approved in 2011. However, cancers vary in response to drugs like vemurafenib, which could even help resistance. The findings suggest that new strategies for overcoming resistance to those types of medications may be useful.
The Cell paper is funded by the Cancer Target Discovery and Development Network (CTD2), which aims to transform cancer genomics data into therapeutic strategies, according to Fu.
Fu claims that research on cancer-associated mutations has been collected. What you need to do is to quickly combine that knowledge into more mechanistic understanding and genotype-directed cancer therapies. This is one technique we can take steps to achieve this goal.
Detecting interactions through energy transfer
Using a robot, researchers can detect altered interactions. Origins of jellyfish and a deep-sea shrimp. Scientists can process when the two proteins come within 10 nanometers of each other in living organisms, using a combination of bioluminescence and fluorescence (BRET or bioluminescence resonance energy transfer). The interaction test can then be performed on a large scale with a robot, on tens of thousands of cancer-associated protein pairs.
Using other biochemical and cellular tests, the research team found that a mutated protein may bind a cancer-associated protein in comparison to its wild type counterpart. A computational algorithm was implemented to investigate mutation-enabled interactions. Finally, researchers also verify whether the two proteins in question, BRAF and KEAP1, actually interact in relevant cancer cells.
The researchers have extended this study and mapped altered protein-protein interactions that are linked to mutations in other cancer-associated genes, such as P53, PTEN, and EGFR, and have made the findings available to the cancer research community. Fu believes that the described approach may also be used to identify neoPPI targets enabled by mutations that are crucial for other human diseases.
Cong Tang, Changfa Shu, Qianjin Li, Danielle Cicka, Xuan Yang, Dacheng Fan, Matthew A. Reyna, Lee A.D. Cooper, Carlos S. Moreno, Sagar Lonial, Fadlo R. Khuri, Yuhong Du, and Suresh S. Ramalingam, among other Emory co-authors. Yiu Huen Tsang, Tsang, and Gordon Mills from OHSU