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
4614 - Predictors of Response to Checkpoint Inhibitors in Naïve and Ipilimumab-Refractory Melanoma
Presenter: Domenico Mallardo
Session: Poster Display session 3
Resources:
Abstract
2901 - IFN-γ/IL-10 ratio as predictive biomarker for response to anti-PD-1 therapy in metastatic melanoma patients
Presenter: Emilio Giunta
Session: Poster Display session 3
Resources:
Abstract
2306 - Multiplex Chromogenic Immunohistochemistry (IHC) for Spatial Analysis of Checkpoint-Positive Tumor Infiltrating Lymphocytes (TILs)
Presenter: Scott Ely
Session: Poster Display session 3
Resources:
Abstract
1678 - The role of PD-L1 expression as a predictive biomarker in advanced renal cell carcinoma: a meta-analysis of randomized clinical trials.
Presenter: Alberto Carretero-Gonzalez
Session: Poster Display session 3
Resources:
Abstract
5138 - Radiomic Features as a Non-invasive Biomarker to Predict Response to Immunotherapy in Recurrent or Metastatic Urothelial Carcinoma
Presenter: Kye Jin Park
Session: Poster Display session 3
Resources:
Abstract
5800 - Integrative combination of high-plex digital profiling techniques and cluster analysis to reveal complex immune biology in the tumor microenvironment of mesothelioma
Presenter: Carmen Ballesteros-Merino
Session: Poster Display session 3
Resources:
Abstract
5736 - Predictive factors of response to immunotherapy in 198 patients with metastatic non-microcytic lung cancer (mNSCLC): real world data from 2 university hospitals in Spain
Presenter: Juan Felipe Cordoba Ortega
Session: Poster Display session 3
Resources:
Abstract
5645 - Evaluating Lung CT Density Changes Among Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) Treated with Thoracic Radiotherapy (TRT) alone or TRT Followed by Combined Ipilimumab (IPI) and Nivolumab (NIVO).
Presenter: Kujtim Latifi
Session: Poster Display session 3
Resources:
Abstract
1540 - Immuno-oncology therapy biomarkers differences between polyoma-virus positive and negative Merkel cell carcinomas
Presenter: Zoran Gatalica
Session: Poster Display session 3
Resources:
Abstract
4538 - Can we improve patient selection for phase 1 clinical trials (Ph1) based on Immuno-Oncology score prognostic index (VIO)?
Presenter: Ignacio Matos Garcia
Session: Poster Display session 3
Resources:
Abstract