Advancing WRN as a synthetic lethal target for microsatellite unstable cancers

Project Summary
Microsatellite instablility (MSI), a class of genetic hypermutability arising from impaired DNA
mismatch repair, contributes to development to types of cancers. While immune checkpoint
blockade (ICB) is effective for some patients, 45-60% of patients do not response to ICB and the
use of these agents can be limited by their toxicity and/or acquired resistance. The pressing need
for further therapies against this large class of cancers inspired our efforts identifying the RecQ
helicase WRN as a synthetic lethal target for MSI cancers. This discovery raises fundamental
questions about how WRN functions to protect the MSI cancers from DNA double strand breaks
and what is the best strategy to implement WRN inhibition to treat MSI cancers. This project seeks
to address these questions by first testing our hypothesis that WRN is required to unwind
secondary DNA structures that are specifically enriched in MSI cells (Aim 1). Furthermore, we will
explore the structure/function relationship of WRN in the context of MSI with a goal of identifying
essential regions to inform drug discovery efforts (Aim 2). Our preliminary data also demonstrated
that WRN inhibition induces a TNFα transcriptional response in MSI cells. These results inspired
our hypothesis that the DNA damage following WRN depletion triggers an innate immune
response in MSI cancers (Aim 3). By integrating functional genomics, biochemical techniques,
DNA repair biology, and in vivo modeling, we seek to define the mechanism underlying the
dependence upon WRN in MSI cells for survival, facilitate rational design of WRN inhibitors, and
promote development of new combination therapies for MSI cancers.
I am a medical oncologist with a background in functional genomics and DNA repair biology. My
long-term goal as a physician-scientist is to lead a basic/translational laboratory studying how
cancers tolerate impaired DNA repair pathways and the vulnerabilities that arise in this context. I
will be primarily mentored by Dr. Adam Bass at the Broad Institute and Dana-Farber Cancer
Institute. Furthermore, my scientific advisory committee composed of Drs. Alan D’Andrea,
Raymond Monnat, Matthew Meyerson, and David Barbie will help guide my scientific and career
development. Coupled with collaborations with Drs. Andre Nussenzweig and Tyler Jacks, a
focused training and career developmental plan, the proposed training plan will help me build the
momentum to launch my career as an independent investigator.

Grant Number: 5K08CA256173-05
NIH Institute/Center: NIH
Principal Investigator: Edmond Chan