Replicative stress in gastroesophageal cancer is associated with chromosomal instability and sensitivity to DNA damage response inhibitors

Pranshu Sahgal; Deepa T Patil; Pratyusha Bala; Zsofia M Sztupinszki; Viktoria Tisza; Sandor Spisak; Anna G Luong; Brandon Huffman; Aurel Prosz; Harshabad Singh; Jean-Bernard Lazaro; Zoltan Szallasi; James M Cleary; Nilay S Sethi

doi:10.1016/j.isci.2023.108169

Replicative stress in gastroesophageal cancer is associated with chromosomal instability and sensitivity to DNA damage response inhibitors

iScience. 2023 Oct 12;26(11):108169. doi: 10.1016/j.isci.2023.108169. eCollection 2023 Nov 17.

Authors

Pranshu Sahgal^{1

2

3

4}, Deepa T Patil⁵, Pratyusha Bala^{1

2

3}, Zsofia M Sztupinszki^{6

4}, Viktoria Tisza^{1

7}, Sandor Spisak^{1

7}, Anna G Luong¹, Brandon Huffman¹, Aurel Prosz⁶, Harshabad Singh^{1

2

8}, Jean-Bernard Lazaro^{9

10}, Zoltan Szallasi^{6

4

11}, James M Cleary^{1

8}, Nilay S Sethi^{1

2

3

8}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02142, USA.
⁴ Computational Health Informatics Program, Boston Children's Hospital, Boston, MA 02115, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁶ Danish Cancer Institute, 2100 Copenhagen, Denmark.
⁷ Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, 1117 Budapest, Hungary.
⁸ Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Center for DNA Damage and Repair (CDDR), Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Department of Bioinformatics and Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1091 Budapest, Hungary.

Abstract

Gastroesophageal adenocarcinoma (GEA) is an aggressive malignancy with chromosomal instability (CIN). To understand adaptive responses enabling DNA damage response (DDR) and CIN, we analyzed matched normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DDR, and p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, such as number of high-level focal amplifications and whole-genome duplication (WGD). Integrating TP53 status, ploidy abnormalities, and DDR markers into a compositive score helped predict GEA cell lines with enhanced sensitivity to Chk1/2 and Wee1 inhibition, either alone or combined with irinotecan (SN38). We demonstrate that Chk1/2 or Wee1 inhibition combined with SN38/irinotecan shows greater anti-tumor activity in human gastric cancer organoids and an in vivo xenograft mouse model. These findings indicate that specific DDR biomarkers and ploidy abnormalities may predict premalignant progression and response to DDR pathway inhibitors.

Keywords: Cancer; Clinical genetics; Oncology.

Grants and funding

K08 DK120930/DK/NIDDK NIH HHS/United States