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

• DOI: 10.1158/0008-5472.c.6513989.v1
• Publication Date: 2023-03-31T14:19:46Z
• Authors: 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

<div>Abstract<p>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 tumors defects in DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors ATR, key regulator response, now clinical development as targeted agents for cancer. Here, we performed large-scale CRISPR interference screen discover genetic determinants resistance ATR (ATRi) cells. Among top hits identified mediators ATRi were UPF2 other components nonsense-mediated decay (NMD) pathway. Loss caused across multiple cell lines. Global proteomic, phosphoproteomic, transcriptional profiling experiments revealed that cell-cycle progression responses altered <i>UPF2</i>-mutant Further studies demonstrated UPF2-depleted cells failed accumulate G<sub>1</sub> following treatment with ATRi. loss also reduced transcription–replication collisions, which has previously been associated thereby suggesting possible mechanism resistance. Our results uncover novel role NMD factors modulating cancer, highlighting unknown may inform use these drugs.</p>Significance:<p>Loss proteins promotes cells, provide combination targets biomarkers improve utility drugs.</p></div>