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Li Lan, MD, PhD

Pronouns

She/Her/Hers

Rank

Associate Professor

Institution

MGH

BWH-MGH Title

Associate Professor

Department

Radiation Oncology

Authors

Li Lan

Understanding and targeting mRNA dependent repair pathway in cancer therapy

It’s important to participate in the Women in Medicine & Science Symposium because a network like this will encourage women at all career stages. My research focuses on breast and ovarian cancer treatment, my lab has published over 70 peer-reviewed research papers in major journals (e.g., Nature, Cancer Discoveries). I filed several patent applications on new therapeutic targets from MGH to improve the treatment of breast and ovarian cancer. As a working mom with kids, as a mentor for students from PhD and CURE programs, I appreciate and strongly believe organization supports for women will benefit whole society.

Abstract

The repair of DNA double-stranded breaks (DSB) is crucial for genomic stability in both normal and cancer cells.  In cancer cells suffering from both intrinsic stresses and extrinsic DNA damage induced by radiation or  chemotherapy, efficient DSB repair is essential for cell survival. Therefore, understanding the mechanisms of DSB repair is critical for exploiting the genomic vulnerabilities of cancer cells. Recent studies by us and others revealed that the DSB in transcribed regions of the genome are repaired through a novel mRNA dependent DNA repair (RDDR) mechanism. Our goal is to target the RDDR pathway in cancer therapy. We identified a specific mRNA methyltransferase, TRDMT1, which is a writer of mRNA methyl-5-cytosine at DNA damage sites and an initiator of RDDR. Using multiple live-cell and biochemical platforms that we developed, we identified lead compounds that specifically inhibit TRDMT1. In breast and ovarian cancers, Homologous recombination (HR)-deficient tumors and over half of HR-proficient tumors may harbor increased mRNA-dependent repair activity, presenting an attractive opportunity for TRDMT1i therapy. Our study may establish the first approach to target this pathway in cancer therapy and broaden the exploitation of genomic instability in both HR-deficient and – proficient tumors.