Scientists at Emory University led by Winship Cancer Institute researcher Haian Fu, PhD, have revealed widespread distortions of a cell’s protein interaction machinery resulting from cancer-causing mutations. They developed a process resembling ground-penetrating radar, for its ability to map the hidden landscape of anticancer drug opportunities.

“One reason why a mutation is tumorigenic is the altered network of protein-protein interactions,” says lead author Haian Fu, PhD, leader of Winship’s Discovery and Developmental Therapeutics Program and professor and chair of pharmacology and chemical biology at Emory University School of Medicine. “The mutation may form a new epitope: a new interaction surface. Such a single protein residue alteration can rewire the cell, leading it down the path of an oncogenic program.”

The researchers have mapped altered protein-protein interactions resulting from mutations in major cancer-associated genes such as BRAF, AKT1, SPOP and SMAD4. They termed these new mutation-enhanced protein-protein interactions “neoPPIs.” The study led to the identification of prevalent neoPPIs in cancer, revealing potential tumor-selective drug targets.

In a case study, researchers show how a common mutation in the gene BRAF — V600E, found in most melanomas, as well as lung and colon cancers — triggers a new interaction between the BRAF-encoded protein and a redox regulator protein KEAP1. Other aspects of how V600E warps cell metabolism have been studied, but this interaction was not previously known.

As a result of the mutation and KEAP1 sequestration, cancer cells produce more of the redox enzyme NQO1. This creates an opportunity to poison the cells by feeding them a compound the enzyme converts into something 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 aimed at the BRAF V600E mutation, such as vemurafenib, which was FDA-approved in 2011. However, cancers vary in response to drugs like vemurafenib and most eventually develop resistance. The information in the study could illuminate new tactics for overcoming resistance to those types of medications, or other weak links in the BRAF pathway.

The results of the research are published in Cell. The co-first authors of the Cell paper are Winship members Xiulei Mo, PhD, assistant professor, and Andrey Ivanov, PhD, professor, as well as instructor Qiankun Niu, PhD, all from the Department of Pharmacology and Chemical Biology.