Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR

Abstract

Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN—knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We found that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we found no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provide the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggest that dual targeting of WRN and ATR might be a useful strategy for treating MSI-H cancers.

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy

“…Our findings in this study suggest that MMR deficiency/MSI-H are also useful biomarkers to guide patient stratification for treatment with ATR inhibitors, which are already extensively tested in clinical trials ( Sundar et al 2017 ; Ngoi et al 2022 ). Our findings are consistent with those from an independent study by the Nussenzweig laboratory ( Zong et al 2023 ), who also found that ATRi preferentially kills MMR-d/MSI-H tumor cells. Both studies suggest that the use of MMR deficiency/MSI-H as biomarkers to guide ATRi therapy may rapidly extend the use of ATRi in patients and improve the treatment of MMR-d/MSI-H tumors.…”

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

“…Another striking example of induced synthetic lethality and antitumor immunity after ATR inhibition has been recently reported regarding Mismatch Repair (MMR) deficient cancer cells [ 112 ]. Also, in tumors with high levels of microsatellite instability (MSI-H) that are characterized by decreased levels of WRN helicase, it has been shown that ATR inhibition may potentiate tumor cell death [ 113 ]. MSI-H tumors may also present mutations in the ARID1A chromatin remodeling protein that plays a substantial role in DNA repair [ 114 ].…”