Mismatch Repair in Cancer Therapy

Despite decades of extensive studies, cancer is still the number 2 leading cause of death in the United States, with a total of 1.7 million new cancer cases and ~600,000 cancer deaths each year. The major problem is that none of the existing therapies can fully eradicate the malignant clone and avoid drug resistance and side effects. Cancer cells defective in MMR are highly resistant to many chemo- and radiation-therapeutic drugs. However, recent studies have shown that tumors defective in MMR respond very well to immunotherapy, but the molecular mechanism is not fully understood.

Our lab is studying the mechanism by which MMR deficiency triggers immunotherapy and identifying/developing molecules specifically targeting to the MMR reaction for cancer cell killing. The latter project includes small molecules and altered MMR proteins capable of triggering cell death during MMR.

Representative Publications

Guan J, Lu C, Jin Q, Lu H, Chen X, Tian L, Zhang Y, Ortega J, Zhang J, Siteni S, Chen M, Gu L, Shay J, Davis A, Chen ZJ, Fu YX, Li GM (2021). MLH1 deficiency-triggered DNA hyper-excision by exonuclease 1 activates the cGAS-STING pathway. Cancer Cell, 39, 109–121.

Lu C, Guan J, Lu S, Jin Q, Rousseau B, Lu T, Stephens D, Zhang H, Zhu J, Yang M, Ren Z, Liang Y, Liu Z, Han C, Liu L, Cao X, Zhang A, Qiao J, Batten K, Chen M, Castrillon DH, Li B, Li GM, Fu YX (2021). DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity. Cancer Cell, 39, 96-108.

Ortega J, Lee GS, Gu L, Yang W, Li GM (2021) Mispair-bound human MutS-MutL complex triggers DNA incisions and activates mismatch repair. Cell Res 2021 Jan 28. doi: 10.1038/s41422-021-00468-y.

Li GM (2008). Mechanisms and functions of DNA mismatch repair. Cell Res 18, 85-98.

Wu J, Gu L, Wang H, Geacintov NE, Li GM (1999). Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis. Mol Cell Biol 19, 8292-8301.