Target set on cancer gene MCL1

April 16, 2012

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 in ," said Todd Golub, director of the Broad's Cancer Program and Charles A. Dana Investigator in 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 , 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 looked for a that accurately predicted which cell lines were dependent on MCL1 for survival. The gene BCL-xL, another gene protective against cell death, was clearly the best predictor. In its presence, can survive even when MCL1 is turned off.

"That was gratifying not only because BCL-xL was a clear winner as a predictive marker, but also because it encodes a protein in the same pathway as MCL1," said Guo Wei, the paper's first author. Wei is a research scientist at the Broad Institute and a research fellow in pediatrics at Dana-Farber. "It's not just right statistically – it also makes sense given the biology."

Drugs targeting BCL-xL are currently in clinical trials. The new study predicts that in cancer cells where both are highly expressed, combination therapies targeting both genes could be effective in treating the tumor.

The researchers also tested almost 3,000 , searching for ones that turned off the expression of MCL1. One of the compounds that this screen revealed was the natural compound triptolide. To find out how triptolide has its effect, the researchers turned to another Broad-created resource: the Connectivity Map, a database researchers can use to connect drugs, genes, and diseases.

"Based on the Connectivity Map, triptolide appears to be a classical inhibitor of transcription, meaning that it should tamp down the expression of all genes," said Wei. "However, it disproportionately affects MCL1. If you give a dose of transcriptional inhibitor, most gene transcripts decrease at a gentle rate, but MCL1 levels decline sharply."

Transcriptional inhibitors like triptolide may be useful tools for probing MCL1 biology, but Golub emphasizes that specific, targeted therapies for MCL1 are also needed. "We used clever chemical genomic approaches to find a way to inhibit MCL1, but the results further our resolve to find more specific MCL1 small molecule inhibitors," Golub, senior author of the study, said.

"The work suggests a path for the clinical development of an MCL1 inhibitor," said Wei. "A number of anti-cancer drugs currently in use have the effect of turning off MCL1 expression. Our study suggests that we're beginning to get a handle on which tumor types might be most responsive to these drugs. And, as newer MCL1-specific drugs are developed, this study suggests the patient population to focus on in clinical trials."

Explore further: First volume of the Cancer Cell Line Encyclopedia made public

Related Stories

First volume of the Cancer Cell Line Encyclopedia made public

March 28, 2012
The goal of cancer treatment is to match the right drug to the right target in the right patient. But before such "personalized" drugs can be developed, more knowledge is needed about specific genomic alterations in cancers ...

Recommended for you

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.