Cancer cell killer also promotes cancer growth in the most aggressive breast cancers
Key Takeaways
A “death-associated” kinase known to help kill cancer cells has been found to sometimes switch roles and actually promote the growth of certain breast and other cancers, according to a new study by researchers at The University of Texas MD Anderson Cancer Center in Houston. Finding a way to inhibit this kinase—death-associated protein kinase 1 (DAPK1)—would be a promising therapy for many of the most aggressive cancers, the researchers concluded.
As its name implies, DAPK1 has well studied roles in activating pathways that stimulate apoptosis in cancer cells. However, the current study, published in The Journal of Clinical Investigation, reported that DAPK1 functions much the opposite in cancers with mutations in the TP53 gene (tumor protein p53).
“This is a little studied kinase that has not been previously focused on for the treatment of cancer,” said the study’s senior author Powel Brown, MD, PhD, Professor and Chair of Clinical Cancer Prevention at MD Anderson Cancer Center. “We discovered a yin and yang phenomenon in terms of DAPK1 function. In normal cells, this protein functions as a death inducer. But in TP53 mutant cells, DAPK1 acts as a critical driver of cancer cell growth.”
DAPK1 was identified while searching for new therapeutic targets in aggressive breast cancers, Dr. Brown said. Breast cancers are often classified according to the presence or absence of three receptor proteins: estrogen receptor (ER), progesterone receptor (PR), and HER2.
Those tumors lacking ER (ER-negative), which account for 30% to 40% of all breast cancers, are typically more aggressive and have a worse prognosis than ER-positive tumors. These include triple receptor-negative breast cancers (TNBCs), which are particularly devastating. Unfortunately, there are few effective treatments for these tumors.
The researchers found that DAPK1 was significantly elevated in ER-negative compared with ER-positive breast cancers. The higher levels of death-associated kinase in this aggressive subtype presented a conundrum that prompted the researchers to investigate further.
They learned that DAPK1 levels did not appear to be directly affected by ER; however, higher expression of DAPK1 did correlate significantly with mutations in TP53, which are abundant in ER-negative breast cancers. This was true especially in TNBCs, 80% or more of which harbor TP53 mutations.
Furthermore, DAPK1 itself appears to be an indicator of poor prognosis. Patients with high levels of DAPK1 had significantly lower survival times compared with those who had low levels of DAPK1, particularly patients with TP53 mutations.
By inhibiting DAPK1 in breast cancer cell lines and mouse models, the researchers learned that cells with TP53 mutations require DAPK1 for their continued growth. Blocking DAPK1 significantly suppressed growth in TP53-mutant cells, but had no effect in those with normal TP53.
The researchers also showed that these results were mirrored in cells from other cancer types, including lung, ovarian, and pancreatic, which contain mutations in TP53. Because TP53 is the most commonly mutated gene across all cancer types (>50%) and is associated with a worse prognosis, inhibiting DAPK1 may be a promising therapeutic goal for a broad group of aggressive tumors.
“This is probably the most exciting finding,” Dr. Brown said. “While a new treatment for triple-negative breast cancers would be a major advance, DAPK1 inhibitors have the potential to be used to treat many different kinds of cancers with TP53 mutations, which include the most lethal cancers without effective treatments.”
Dr. Brown is eager to work on developing DAPK1 inhibitors as potential therapies. He hopes to have one in clinical trials within 3 years. Additionally, his lab is currently testing DAPK1 inhibition in combination with various types of chemotherapy to determine if additive benefits can be achieved with other targeted therapies.