Lung squamous cell carcinoma (LUSC) is a type of non-small-cell lung cancer that starts in squamous cells, which are flat cells lining the airways in the lungs. This type of lung cancer is often linked to a history of smoking and makes up about one-third of all lung cancer cases.
Unlike other types of lung cancer, patients with LUSC haven’t benefitted much from targeted therapies. Targeted therapies focus on fixing changes in a tumor’s DNA and usually cause fewer side effects because they target the cancer cells directly instead of harming healthy cells. Unfortunately, LUSC has few mutations in cancer-causing genes, so these treatments aren’t as effective.
Dr. Milica Momcilovic, an Assistant Professor in the Department of Medicine, Pulmonary and Critical Care at the University of California, Los Angeles, is studying how squamous cell carcinomas become resistant to targeted therapy. With a Lung Cancer Discovery Award from the American Lung Association, she is exploring whether anti-estrogen targeted therapy could help treat some LUSCs in women.
“By 2024, it’s estimated that about half of the 125,000 lung cancer deaths in the U.S. will be women,” Dr. Momcilovic explained. “But we don’t have treatments specifically designed for female patients. That is mostly because we don’t fully understand the differences between how men and women respond to treatment.”
Dr. Momcilovic’s goal is to develop better, personalized treatments for lung cancer by understanding each patient’s unique tumor characteristics and finding the right therapy for them. She hopes to figure out why some treatments work for certain patients but not others, identify biomarkers that can predict which treatments will work, and discover new combination therapies that might be more effective than current standard-of-care treatments.
She is studying lung cancer cells using both lab experiments and mouse models. Her techniques combine molecular biology, biochemistry as well as imaging like CT scans to learn how cancer cells function, grow and respond to treatments.
One protein Dr. Momcilovic is interested in studying is called mTOR, which controls cell functions like cell growth and survival. mTOR is often not working properly in cancer cells. She recently found that a drug called TAK228, which blocks mTOR, slows growth of LUSC tumors. TAK228 is currently being tested in clinical trials with patients. However, some LUSC tumors still resist TAK228 and keep growing and despite the drug’s effects on mTOR.
Dr. Momcilovic also discovered that male mice are more sensitive to TAK228’s mTOR blocking abilities than female mice. “We think this is because estrogen levels are higher in female mice compared with male mice,” she said. Further tests showed that using an anti-estrogen drug therapy (Letrozole) made LUSC tumors in female mice more sensitive to TAK228, showing that estrogen might be linked to resistance.
Dr. Momcilovic and her team identified a gene called GPER, which keeps mTOR cell signaling pathway active. “With the ALA grant, we will look more closely at how GPER, and other molecules contribute to therapy resistance of mTOR in females,” she said.
“This research is important because resistance to targeted therapy is a major challenge to getting effective long-term response in lung cancer,” Dr. Momcilovic said. “Identifying new strategies to overcome therapy resistance would lead to longer and more efficient therapeutic responses in female lung cancer patients. This could lead to increased survival and improved quality of life for these patients.”
Blog last updated: February 12, 2025
