Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2

Patrick C. O'Leary, Huadong Chen, Yagmur U. Doruk, Tess Williamson, Benjamin Polacco, Andrew S. McNeal, Tanushree Shenoy, Nupura Kale, Julia Carnevale, Erica Stevenson, David A. Quigley, Jonathan Chou, Felix Y. Feng, Danielle L. Swaney, Nevan J. Krogan, Minkyu Kim, Morgan E. Diolaiti, Alan Ashworth

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a largescale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense- mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in UPF2-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G1 following treatment with ATRi. UPF2 loss also reduced transcription-replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs.

Original languageEnglish (US)
Pages (from-to)3950-3961
Number of pages12
JournalCancer Research
Volume82
Issue number21
DOIs
StatePublished - Nov 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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