Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer

Feifei Zhang; Varun Sahu; Ke Peng; Yichen Wang; Tianxia Li; Pratyusha Bala; Daulet Aitymbayev; Pranshu Sahgal; Antje Schaefer; Channing J Der; Sandra Ryeom; Sam Yoon; Nilay Sethi; Adam J Bass; Haisheng Zhang

doi:10.1136/gutjnl-2023-329686

Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer

Gut. 2024 Apr 15:gutjnl-2023-329686. doi: 10.1136/gutjnl-2023-329686. Online ahead of print.

Authors

Feifei Zhang^#^{1

2}, Varun Sahu^#^{3

4}, Ke Peng^{2

5}, Yichen Wang^{2

6}, Tianxia Li³, Pratyusha Bala², Daulet Aitymbayev², Pranshu Sahgal², Antje Schaefer^{7

8}, Channing J Der^{8

9}, Sandra Ryeom¹⁰, Sam Yoon¹⁰, Nilay Sethi², Adam J Bass^#^{11

12}, Haisheng Zhang^#^{13

2

14}

Affiliations

¹ Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
³ Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
⁴ Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, USA.
⁵ Department of Medical Oncology, Fudan University, Shanghai, China.
⁶ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Universty of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁸ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁹ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹⁰ Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA.
¹¹ Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA eslite3000@gmail.com ab5147@cumc.columbia.edu.
¹² Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
¹³ Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China eslite3000@gmail.com ab5147@cumc.columbia.edu.
¹⁴ Signet Therapeutics, Shenzhen, China.

^# Contributed equally.

PMID: 38621923
DOI: 10.1136/gutjnl-2023-329686

Abstract

Objective: Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations.

Design: We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC.

Results: We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth.

Conclusion: These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.

Keywords: gastric cancer; molecular oncology.