The Story of DDR2
DDR2 defines rare, but treatable, cancer subtypes.
Cancer is not a single disease. The kinds of cancer were once defined solely by affected body part, such as skin, colon, lung, or brain. Then cancers began to be described by their location within the architecture of an organ, such as a specific tissue with a specific orientation. The most common type of breast cancer, for example, occurs in the epithelium (lining) of the ducts where milk is secreted. Some cancers are described by the cell types in which they arise, such as T-cell leukemia of the blood or an astrocytoma in the brain.
Increasingly, researchers are classifying cancers not by body part, but by the genes that harbor mutations that send certain cells down a pathway of runaway proliferation. In fact, the same mutant genes may cause or contribute to cancers in very different parts of the body. That’s the case for DDR2, which stands for “discoid domain receptor tyrosine kinase 2.” In certain subtypes of head and neck, lung, and breast cancers, abnormal DDR2 protein is synthesized in cancer cells at the edges of a tumor. Although DDR2 is mutant in relatively few cases of cancer, its effects are well understood and an existing cancer drug, dasatinib (marketed as Sprycei) is effective in treating cancers in which it is involved.
You could call DDR2 a late bloomer, because DDR2 mutations intervene late in cancer. It typically takes many genetic changes to propel a cancer in a way that it can grow, invade, and spread (metastasize) while avoiding attack from the person’s immune system. Before cancer cells enter the bloodstream, they invade locally, dividing more frequently than healthy surrounding cells and piling up on one another to form an abnormal growth.
To invade tissue, however, a growing cancer must push through layers of healthy cells as well as the stuff between cells, called the extracellular matrix or ECM. This is where DDR2 comes in. Much of the matrix consists of collagen, which forms a scaffolding of highly symmetrical fibrils. The pattern in which collagen fibrils are arrayed between cells is distinctive and essential for those cells to function. Collagen fibrils in the neighborhood of a healthy cell run parallel to each other alongside the cell. This cellular architecture suppresses cell division.
When DDR2 is mutant, the encoded protein is changed in a way that enables collagen fibrils to align perpendicular to the cell. This positioning forms tubes that can provide passageways for cancer cells to move, like couples at a wedding lining up and parting so that the bride and groom can walk through.
Through these tubes, common to all cells, but deranged in cancer, messages from outside the cell are transmitted inside by triggering a chain reaction of adding phosphate groups to a series of molecules, like a bucket brigade down the wedding aisle. (A phosphate is a phosphorus atom bonded to three oxygen atoms.) Ultimately when the message from this bucket brigade, technically termed signal transduction, reaches the nucleus in a cell with a DDR2 mutation, cell division is triggered.
Cancers related to DDR2 are relatively rare. For example, non-small cell lung cancer (NSCLC) accounts for 80 percent of lung cancers, and 30 percent of those affect squamous cells (flat epithelial, or lining cells). Of the squamous cell lung cancers, 3,8 percent are linked to mutations in DDR2-about 1,000 to 2,000 cases per year.
These cancers occur in the upper parts of the respiratory tract, mostly in the bronchi that attach the trachea (windpipe) to the lungs. More males are affected than females, and more smokers than non-smokers. These cancers are typically detected in early stages because they are more accessible to sampling, and cause persistent cough, wheezing, and bloody sputum. DDR2 lung cancers are slow-growing compared to other forms.
Matthew Meyerson, M.D., Ph.D., and professor of pathology at the Dana Farber Cancer Institute, led the team that discovered DDR2 mutations in NSCLC and identified dasatinib as a treatment. “As a percentage of the millions of people who get cancer each year it is small, but cancer therapy is going more in the direction of personalized medicine as we learn more and more about the complicated biology of each tumor,” he said.
DDR2 mutations also arise in cancerous breast tumors that are very dense, because the density is the result of abundant collagen. Excess collagen makes mammograms very difficult to read and also contributes directly to the disease.
Squamous cell cancers of the head and neck may have DDR2 mutations. About half of these cancers have already spread to the lymph nodes at the time of diagnosis. After surgery, however, the cancer recurs in 20 to 30 percent of patients, and typically does not respond to conventional drugs. Researchers at the University of Pittsburgh Cancer Institute and Yale University School of Medicine discovered that some of these recurrent cancers have DDR2 mutations that were not present in the original tumors, and may respond to dasatinib.