SMALL CELL LUNG CANCER is aggressive and often spreads before it’s detected. About 70% of patients have metastatic cancer at diagnosis, and the five-year survival rate remains roughly 7% .Now Duke University School of Medicine researchers have identified a promising new strategy to fight this deadly disease :
Combining low doses of two cancer drugs to overwhelm tumors that have spread throughout the body .
In a study published in Cell Reports, the team found that pairing the FDA-approved leukemia drug ASCIMINIB with an experimental ATR inhibitor was far more effective at killing metastatic small cell lung cancer cells than either drug alone .
The combination dramatically slowed the growth of metastatic tumors in cell lines and in mouse models .
" Based on these discoveries and our previous success in translating research to the clinic, we believe this work will lead to effective new therapies for patients with metastatic SMALL CELL LUNG CANCER ," said senior author Ann Marie Pendergast, PhD, the Anthony R. Means Cancer Biology Distinguished Professor .
BUILDING ON PREVIOUS SUCCESS
Pendergast's laboratory had previously shown that ASCIMINIB, which inhibits an enzyme called ABL kinase, can block the growth of metastatic tumors in other cancers . That work helped lay the foundation for a Duke clinical trial testing the drug in patients with HER2-positive breast cancer that has spread to the brain .
When the researchers tested asciminib in models of metastatic SMALL CELL LUNG CANCER, the results stood out .
" With the single treatment, the results were more striking for small cell lung cancer than for any other tumor we've studied, " Pendergast said . “ ABL kinase inhibition alone decreased metastatic dissemination of multiple subtypes of SMALL CELL LUNG CANCER, which is what you want because you don't want one subtype to become another subtype that might be more difficult to treat .”
Seeking to understand why this strategy worked so dramatically for this cancer, the team found that asciminib induced DNA damage and disrupted the cancer cells' ability to accurately copy their DNA, creating genetic stress .
Cancer cells normally rely on a protein called ATR to help them survive that stress and repair the resulting damage . The researchers reasoned that simultaneously blocking ATR could remove that safety net .
When they tested it, the combination left cancer cells unable to cope with accumulating DNA damage and dramatically reduced their ability to grow and spread .
COLLISIÓNS THAT LEADE TO CELL DEATH
The team wanted to understand in depth why the DNA damage happened . They suspected that the leukemia drug might be regulating how cells resolve obstacles called R-loops that can form at sites where the damaged DNA is being being read and converted into messenger RNA .To find out if they were correct, Pendergast joined forces with Lee Zou, PhD, chair of the Department of Pharmacology and Cancer Biology, and Li Lan, PhD, associate professor of molecular genetics and microbiology . They’re both experts in biological processes involved in DNA damage and repair, including the formation and clearance of R-loops .
As cancer cells raced to copy their genetic material, the DNA-copying machinery repeatedly crashed into these obstacles, triggering DNA damage and cellular stress . Using expertise from all three labs, the team discovered that the drug indeed led to an increase in collisions caused by R-loops . A PhD student in the Pendergast lab, Kevin M. Scott, learned a specialized technique from the Zou and Lan labs that he used to visualize these molecular collisions and confirm that the drug was increasing them .
Because ASCIMINIB is already FDA-approved for leukemia, and ATR inhibitors are being tested in clinical trials, the findings could be translated more quickly than a treatment strategy that depends on developing an entirely new drug .
The low doses involved are a plus in the case of ATR inhibitors, which unfortunately cause side effects at higher doses, Pendergast said .
In July, Pendergast and Lan received a five-year National Institutes of Health grant to dissect the molecular mechanisms that regulate DNA damage and repair in small cell lung cancer and move these discoveries closer to the clinic . Drawing on Duke's close collaboration between laboratory scientists and clinical researchers, the team will test the approach in preclinical models and patient-derived tumor samples, study how it blocks cancer spread, and identify the patients most likely to benefit from new combination therapies .
Funding: The National Institutes of Health ( National Cancer Institure ), the Lung Cancer Research Foundation, and the Duke Cancer Institute Cancer Center Support grant .
Other Duke authors : Jing Jin Gu, Arijit Ghosh, Roberto H. Barbier, Douglas C. Rouse, Jacob P. Hoj, Michael W. Caminear, Fengqi Zhang, Boya Gao, and Margaret W. Barbier .
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