Abstract 1787
Background
Jumonji domain-containing protein 2A (JMJD2A), belonging to the JMJD2 family of histone lysine demethylases, has been implicated in tumorigenesis. However, its expression profile and role in drug resistance of gastric cancer remains unknown. Previous studies show that docetaxel, cisplatin, and S-1 (DCS) therapy has a high response rate in patients with metastatic gastric cancer, but acquired drug resistance is often observed. In this study, we investigated the role of JMJD2A in drug susceptibility of DCS therapy in patients with gastric cancer, and its clinical relevance in gastric cancer.
Methods
siRNA-mediated downregulation of 14 relevant genes from previously identified gene signatures was performed to identify functional factor to modulate drug susceptibility in DCS therapy. In 34 clinical tissues with metastatic gastric cancer, we examined whether JMJD2A expression predicted tumor regression rate in patients. Furthermore, the downstream effects of JMJD2A on drug susceptibility were analyzed by whole-gene expression array and immunoprecipitation.
Results
After specific silencing of 14 candidate genes, inhibition of JMJD2A induced significant drug resistance in three anti-cancer drugs; IC50values for 5-FU, cisplatin, and docetaxel were 15.3-, 2.7-, and 4.0-fold increased, respectively. Overexpressed JMJD2A was universally expressed in 12 gastric cancer cell lines, positively correlated with tumor regression rate in DCS therapy. JMJD2A is physically associated with histone lysine demethylation. By analysis of downstream effect of JMJD2A, cooperation of Coiled-coil domain containing 8 (CCDC8) was identified, using whole-gene expression analysis. Direct interaction of CCDC8 and JMJD2A was verified by immunoprecipitation. Of note, inhibition of CCDC8 also induced significant drug resistance in docetaxel, cisplatin, and S-1.
Conclusions
JMJD2A sensitizes gastric cancer to combination chemotherapy of S-1, cisplatin, and docetaxel by cooperating CCDC8, and JMJD2A/CCDC8 would be a potential biomarker and therapeutic target.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
JSPS KAKENHI.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2171 - CCND1 Amplification Contributes to Immunosuppression in Head and Neck Squamous Cell Carcinoma and the Association with a Poor Response to Immune Checkpoint Inhibitors
Presenter: Chloe Huang
Session: Poster Display session 3
Resources:
Abstract
2624 - Efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer patients with sensitive genes mutation
Presenter: Hui-Juan Cui
Session: Poster Display session 3
Resources:
Abstract
3494 - Neutrophil to Lymphocyte Ratio (NLR) kinetics as predictors of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (NSCLC) patients treated with nivolumab (N).
Presenter: Audrey Simonaggio
Session: Poster Display session 3
Resources:
Abstract
3964 - Predictive markers of checkpoint inhibitor activity in adult metastatic solid tumours
Presenter: Alexandra Pender
Session: Poster Display session 3
Resources:
Abstract
3041 - Blood-based TMB (bTMB) correlates with tissue-based TMB (tTMB) in a multi-cancer Phase I IO Cohort
Presenter: Daniel Araujo
Session: Poster Display session 3
Resources:
Abstract
3910 - Analysis of Molecular Profile Complexities for Immunotherapy Decision Support
Presenter: Robert Dóczi
Session: Poster Display session 3
Resources:
Abstract
4836 - The Role of Tumor Neoantigens in the Differential Response to Immunotherapy (IO) in EGFR and BRAF Mutated Lung Cancers - Quantity or Quality?
Presenter: Katrina Case
Session: Poster Display session 3
Resources:
Abstract
1929 - Impact of previous corticosteroid (CS) exposure on efficacy of Programmed Cell Death-(Ligand) 1 blockade in patients with advanced Non-Small-Cell Lung Cancer (NSCLC): a single Center retrospective analysis
Presenter: Fabrizio Nelli
Session: Poster Display session 3
Resources:
Abstract
2601 - Comparison 18F-FDG-PET/CT criteria for prediction of therapy response and clinical outcome in patients with metastatic melanoma treated with Ipilimumab and PD-1 inhibitors
Presenter: Sabrina Vari
Session: Poster Display session 3
Resources:
Abstract
3628 - Predictive model for survival in advanced non-small-cell lung cancer (NSCLC) treated with frontline pembrolizumab
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 3
Resources:
Abstract