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Ludwig Harvard study identifies novel mechanism driving triple-negative breast cancers – and potential targets for therapy

AUGUST 3, 2020, New York— A study from the Ludwig Center at Harvard has identified a previously unrecognized molecular mechanism that drives a large proportion of triple-negative breast cancers and shown that existing targeted therapies can disrupt it, extending survival in mouse models of the malignancy.

Led by Ludwig Harvard investigators Alex Toker and Hui Liu and their colleague Lewis Cantley of the Weill Cornell Medical College in New York, the study describes how the loss of the tumor suppressor protein, INPP4B, activates a growth-promoting signaling pathway that drives the proliferation of triple-negative breast cancer (TNBC) cells. The findings are reported in the August 3 issue of Cancer Discovery.

“The impetus for our study was to develop a model for testing new therapeutic approaches for triple-negative breast cancer, which is an important focus of the Ludwig Center at Harvard,” says Toker. “There’s been a pressing need for some time to understand the molecular basis of this cancer and find precise targets for new therapies.”

The extraordinary genetic heterogeneity of TNBC has long complicated the development of targeted therapies for the cancer, which is still primarily treated with chemotherapy. But it is known that about 80% of all TNBC tumors are characterized by loss of INPP4B expression.

Cantley’s laboratory demonstrated more than a decade ago that INPP4B is a tumor suppressor and that its loss aberrantly activates a classical growth signaling pathway in cells that is mediated by the proteins PI3 kinase (PI3K) and AKT. The former transmits its signals by tacking a molecule known as a phosphate onto specific lipids, creating phospholipids that are incorporated into membranes. INPP4B, a phosphatase, removes those phosphates.

“You can think of the activation of PI3 kinase and AKT as an ‘on’ pathway that promotes cell proliferation and survival,” explains Toker. “The reverse reaction that is carried out by phosphatases is essentially a termination signal.”

To further explore how INPP4B loss drives cell proliferation, Liu engineered a mouse model of TNBC to lack one or both of its INPP4B genes. The lower the levels of INPP4B, the researchers showed, the greater the incidence of tumors. As expected, cells from such tumors displayed an abnormal activation of PI3K and AKT.

But the researchers were surprised to find that an additional pathway that drives cell proliferation—one triggered by a cell-surface protein known as the EGF receptor—was also potently active in these tumors. This pathway signals through proteins called MEK and MAP kinase inside cells.

After it is activated, the EGF receptor is often pinched off and internalized on bladder-like vesicles in cells. The internalized receptor then continues transmitting its growth-promoting signals until it is either returned to the cell surface or degraded and digested. This happens relatively swiftly in normal cells.

The researchers discovered that the loss of INPP4B alters the phospholipid composition of intracellular vesicles and suspends the movement of EGF receptor and its processing within the cell. This extended delay prolongs signaling by the EGF receptor—effectively fueling an additional and abnormal pathway conducive to cell proliferation.

Toker, Liu, Cantley and colleagues reasoned that this might make INPP4B-deficient tumors susceptible to drugs that target MEK and PI3K. Experiments on their mouse models and in TNBC cell lines revealed that such tumors were indeed far more sensitive to drugs that inhibit these signaling proteins.

“We found a number of drugs either approved or being evaluated in clinical trials that target the PI3K and MAPK pathways improved overall survival of the mice,” said Toker. The most effective, it turned out, was an inhibitor of PI3K that has already been approved for the treatment of estrogen receptor-positive breast cancers.

The discovery could, with further development, add a new, more targeted therapy to the incipient arsenal of targeted drugs to treat TNBC. Meanwhile, the researchers are using their mouse model to further explore the mechanism by which INPP4B loss promotes vesicle retention and constitutive EGF receptor signaling in TNBC cells.

Alex Toker is a Professor of Pathology at Beth Israel Deaconess Medical Center and Harvard Medical School; Hui Liu is an instructor in his laboratory.

Lewis Cantley is Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College in New York.


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