Abstract 1493P
Background
Resistance to anti-HER2 drugs in HER2 amplified GC represents a limitation for precision medicine. In our HER2 amplified models, PI3K pathway activated NRF2, a master regulator of oxidative stress, inducing antiHER2-drug resistance. The aim of this study was to assess the role of chromosomal alterations and their relation with NRF2 antioxidant mechanism responsible for resistance in our resistant models.
Methods
The OE19 GC cell line and its lapatinib resistant subclones were used for this study. DNA and RNA extraction was carried out according to the manufacturers (ThermoFisher and Roche respectively). Gene expression profile was performed by Clariom™ S Assay (Applied Biosystems™). Chromosomal aberrations analysis was carried out with CytoScan HD Array (Applied Biosystems™) and analyzed with Chromosome Analysis Suite (ChAS) software. The results were analyzed with R. Cytoscape and the plug-in ClueGO, that integrates the terms Gene Ontology with KEGG and Reactome, were used to detect the activated pathways.
Results
Gene expression profile underlined a significantly higher expression of ARE-bearing genes, involved in the cellular response to oxidative stress, demonstrating a relevant role of NRF2 in antiHER2 resistance in our models. The chromosomal aberrations analysis showed an increase in genomic instability among resistant cells. In particular, the amplification of the ferritin light chain (FTL) gene (19q13.33) was detected with an increase of FTL/FTH (ferritin high chain) expression ratio that confers control of the oxidative stress promoting survival. The integrated analysis suggests that the activation of two antioxidative systems, NRF2, and ferritin, could effectively modulate oxidative stress causing antiHER2 resistance. The loss of CDKN1A (6p21.2) was also detected, confirming the worse proliferative phenotype.
Conclusions
Our results confirm the relevant role of control of oxidative stress in antiHER2 resistance. The integrated genomic and transcriptomic analysis would improve our understanding of the mechanisms of resistance leading to implement precision medicine.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
VG was supported by the ESMO 2014 fellowship program, and by Rio Hortega contract CM18/00241 from the Carlos III Health Institute; TF is supported by Joan Rodes contract 17/ 00026 from the Carlos III Health Institute. NT was supported by Rio Hortega contract CM15/00246 from the Instituto de Salud Carlos III and by the ESMO 2013 fellowship program; DR was supported by Joan Rodes contract 16/00040 from the Instituto de Salud Carlos III. JMC was supported by a Rio Hortega SEOM contract from the Instituto de Salud Carlos III 2019. SZ has a CA18/00042 contract for bio-informaticians from the Instituto de Salud Carlos III.
Disclosure
A. Cervantes: Honoraria (institution): Genentech; Honoraria (institution): Merck Serono; Honoraria (institution): BMS; Honoraria (institution): MSD; Honoraria (institution): Roche; Honoraria (institution): Beigene; Honoraria (institution): Bayer; Honoraria (institution): Servier; Honoraria (institution): Lilly; Honoraria (institution): Novartis; Honoraria (institution): Takeda; Honoraria (institution): Astellas; Honoraria (institution): Fibrogen. All other authors have declared no conflicts of interest.