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
1885 - Factors associated with disease progression in patients treated with trametinib in combination with dabrafenib for unresectable advanced BRAFV600-mutant melanoma: an open label, non randomized study
Presenter: Philippe Saiag
Session: Poster Display session 3
Resources:
Abstract
5259 - Integrative RNAseq and Target panel sequencing reveals common and distinct innate and adaptive resistance mechanisms to BRAF inhibitors
Presenter: Phil Cheng
Session: Poster Display session 3
Resources:
Abstract
5619 - Effective treatment with T-VEC monotherapy in Stage IIIB/C-IVM1a Melanoma of the Head & Neck Region
Presenter: Viola Franke
Session: Poster Display session 3
Resources:
Abstract
5666 - Re-introduction of T-VEC Monotherapy in Recurrent Stage IIIB/C-IVM1a melanoma is effective
Presenter: Viola Franke
Session: Poster Display session 3
Resources:
Abstract
4117 - Efficacy of talimogene laherparepvec (T-VEC) in melanoma patients (pts) with locoregional (LR) recurrence, including in-transit metastases (ITM): subgroup analysis of the phase 3 OPTiM study
Presenter: Mark Middleton
Session: Poster Display session 3
Resources:
Abstract
5303 - Real Life Use of Talimogene Laherparepvec in Melanoma in Centers in Austria and Switzeland
Presenter: Christoph Hoeller
Session: Poster Display session 3
Resources:
Abstract
4130 - Outcomes of advanced melanoma patients who discontinued pembrolizumab (pembro) after complete response (CR) in the French early access program (EAP)
Presenter: Philippe Saiag
Session: Poster Display session 3
Resources:
Abstract
2050 - Outcome of patients with elevated LDH treated with first-line targeted therapy (TT) or PD-1 based immune checkpoint inhibitors (ICI)
Presenter: Sarah Knispel
Session: Poster Display session 3
Resources:
Abstract
1618 - Comparative-Effectiveness of Pembrolizumab vs. Nivolumab for Patients with Metastatic Melanoma
Presenter: Justin Moser
Session: Poster Display session 3
Resources:
Abstract
3556 - Long-term efficacy of combination nivolumab and ipilimumab for first-line treatment of advanced melanoma: a network meta-analysis
Presenter: Peter Mohr
Session: Poster Display session 3
Resources:
Abstract