Milica Momcilovic, MD, PhD

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer that has few mutations in cancer-causing genes that can be targeted with selective inhibitor medications. This lack of clear genetic drivers in LUSC results in a lack of targeted therapies for these patients. MTOR is a protein that controls cell functions like cell division and survival and is often deregulated in cancers. We have recently found that a drug known as TAK228, which inhibits mTOR, stalls growth of LUSC tumors. TAK228 is currently being evaluated in patients in a phase II clinical trial. However, a subset of LUSC tumors remain resistant to TAK228 and maintain tumor growth and proliferation despite the drug’s intended effects on mTOR. We identified a sex-specific effect of TAK228 in which male mice were significantly more sensitive to mTOR inhibition than females. Additional experiments showed that the anti-estrogen therapy (Letrozole) sensitized LUSCs in female mice to TAK228 treatment, demonstrating an estrogen-related link to resistance.

Update: We are discovering that lowering estrogen in mouse models of lung squamous cell carcinoma (LUSC) improves responses to targeted therapy. Using mouse models of LUSC, we show that combination of TAK228, a small molecule that targets mTOR pathway, and Letrozole, an FDA-approved drug that lowers estrogen levels, significantly reduces tumor growth. Additionally, data using mouse models with intact immune system suggests that reducing estrogen signaling has a potentially positive effect on tumor immune microenvironment.