A research team pursuing one of the most commonly altered genes in cancer has laid a critical foundation for understanding this gene that could point the way toward developing drugs against it. A recent study of cancer genetics pointed to the gene MCL1, which encodes a protein that helps keep cells alive. The new research pinpoints compounds that repress MCL1's activity and highlights an important companion gene that predicts if a tumor is dependent upon MCL1 for survival. Together, these tools suggest a path toward new therapeutics directed at MCL1.
"It was not immediately obvious that MCL1 was such an attractive therapeutic target in cancer," said Todd Golub, director of the Broad's Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. Golub is also a professor at Harvard Medical School and investigator at Howard Hughes Medical Institute. "But once it became clear that MCL1 was something that we wanted to turn off in tumor cells, we faced two additional problems: we didn't know which tumors depend on it for survival and there wasn't an obvious path to drug discovery. This paper addresses those two challenges."
In a paper appearing in the April issue of the journal Cancer Cell, Golub and colleagues from the Broad Institute and Dana-Farber identify several chemical compounds that tamp down the expression of the MCL1 gene and describe the relationship between MCL1 and a related pro-survival gene, BCL-xL. The research team leveraged several critical Broad Institute resources, including the recently published Cancer Cell Line Encyclopedia (CCLE) and RNAi screening capabilities, to better understand how to target MCL1.
MCL1 is frequently amplified in human cancer, meaning that multiple copies of the gene are often present in tumors. The research team suppressed MCL1 in cancer cell lines, allowing them to determine which ones depended on MCL1 for survival. The researchers then
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Broad Institute of MIT and Harvard