Quantitative Chemical-Genetic Interaction Map Connects Gene Alterations to Drug Responses

February 05, 2015

In a recent Cancer Discovery report, CTD2 researchers at the University of California in San Francisco developed a new quantitative chemical-genetic interaction mapping approach to evaluate drug sensitivity or resistance in isogenic cell lines. Performing a high-throughput screen with isogenic cell lines allowed the researchers to explore the impact of a panel of emerging and established drugs on cells overexpressing a single cancer-associated gene in isolation. The use of isogenic cell lines also helped identify synthetic lethal relationships, or tumor gene dependencies.

The researchers created a chemical-genetic interaction map and identified synthetic lethal relationships for oncogenes that have not been targeted directly. For example, MYC encodes a transcription factor that is overexpressed in many tumors, including the most aggressive form of breast cancer known as triple-negative breast cancer. The chemical-genetic interaction map showed that MYC overexpression confers resistance to six inhibitors of the v-Akt Murine Thymoma Viral Oncogene/Phosphoinositide 3-kinase/mammalian target of rapamycin (AKT/PI3K/mTOR) pathway. Cells overexpressing MYC were sensitive to Dasatinib, an FDA approved tyrosine kinase inhibitor. Proteomic analysis suggested that this sensitivity may be caused by a synthetic lethal relationship between MYC and Lck/Yes novel tyrosine kinase (LYN), which is a target of Dasatinib. The researchers, in collaboration with researchers from the Broad Institute, confirmed a link between MYC and LYN within breast cancer tissue by examining data from The Cancer Genome Atlas. The method described above is a new systems biology approach that will help functionally characterize genomic alterations in cancer and advance precision medicine.

Last updated: June 29, 2020