Scientists target molecular 'addiction' in triple-negative breast cancer

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In a discovery that could lead to improved treatments for patients with an aggressive type of breast cancer that has few treatment options, scientists at Dana-Farber Cancer Institute have identified a molecular weakness in these cancer cells that can be exploited by targeted inhibitors.

While triple-negative breast tumor cells are genetically complex and driven by many different mutations, the scientists report in Cell that they are all strongly dependent on – in fact, “addicted to,” – a single “Achilles cluster” of genes under the control of a master regulator, CDK7.

When the researchers used a designer compound to block CDK7, it quickly killed triple-negative breast cancer cells in the laboratory and in mouse tumors seeded by tumor tissues from patients. This underscored how sensitive the cancer cells are to the loss of CDK7’s signals that trigger the malignant behavior of the cells via the vital gene cluster.

“It is remarkable to see this kind of efficacy with a single agent in this disease,” said Jean Zhao, PhD, a Dana-Farber cancer biologist who is co-senior author along with Nathanael Gray, PhD and Richard Young, PhD at MIT. “CDK inhibition represents a highly promising therapy for this subtype of cancer.”

Both Gray and Young are founders of Syros Pharmaceuticals, which has licensed intellectual property rights on the CDK inhibitors from Dana-Farber for drug development.

The investigators targeted the CDK7 molecule using THZ1, an inhibitor compound recently developed in the Gray laboratory, and THZ2, a modified version with a longer half-life. Zhao said the experimental results are a proof-of-principle that serves as a new lead in how to attack triple-negative breast cancer, which isn’t vulnerable to currently available precision-targeted drugs.

About 15 to 20 percent of breast cancers are triple-negative, meaning they lack receptors for estrogen, progesterone, or excessive HER2/neu signaling that fuels most breast cancers. As a result, they aren’t amenable to treatment with endocrine-blocking drugs or trastuzumab (Herceptin), and are highly aggressive. They tend to occur more often in younger women and African American women. Most breast cancers caused by the mutant BRCA1 gene are triple-negative or a closely related type, basal-like.

Unlike many cancers, the growth of triple-negative breast cancers isn’t driven by one or two key genetic mutations to which therapy can be targeted. Instead, the tumors are highly heterogeneous – made up of cells with a wide array of genetic perpetrators differing from one cell to another, and no single kingpin to go after.

But despite the cells’ complexity, Zhao and her colleagues hypothesized that they all had a common mechanism for reading the DNA instructions in their genes, and that this mechanism – called a “transcriptional program” – might be blocked by disabling a key master regulator of the process. It turned out that this regulator, CDK7, is so crucial that knocking it out suppresses the growth and survival of triple-negative cancer cells – but not cells of other breast cancers that are fueled by hormones.

The researchers showed that CDK7 inhibitors acted selectively without causing toxicity even though normal body cells also use CDK7 for transcription. That’s because triple-negative cancer cells are so exquisitely sensitive to CDK7 function, and that it can be reduced to halt the cancer without harming normal cells, the researchers said.

Their discovery that a genetically heterogeneous type of cancer is dependent on a common transcriptional program that can be inhibited may be applicable to other hard-to-treat cancers, said the investigators.

First authors of the report are Yubao Wang and Tinghu Zhang, PhD, of Dana-Farber and Harvard Medical School, and Nicholas Kwiatkowski, PhD, of Whitehead Institute for Biomedical Research.

The research was supported by National Institutes of Health grant RO1CA179483-01 and NIH/National Cancer Institute grant P50CA168504.

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Breast Cancer
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