Abstract 4980
Background
Personalized treatment for gastric cancer (GC) represents a big challenge. HER2 is an important driver in 7-34% of cases, playing a relevant role in cell growth and survival. Trastuzumab (T), when combined with chemotherapy, improves survival. No further anti HER2 drugs demonstrated clinical benefit. Resistance to treatment is a serious problem.
Methods
OE 19 and NCI N87, HER2+ GC cell lines, were treated with increasing doses of Lapatinib (L) and T to obtain resistant clones. These were isolated and characterized by performing mutational analysis by Sequenom MassArray and Western blot (WB) to evaluate protein expression. Genome-wide expression profile was conducted. Inhibition of the altered pathways was performed with specific drugs and siRNA to verify if those alterations were responsible for resistance. In vivoexperiment was performed to corroborate the obtained results. A retrospective cohort of HER2 amplified patients treated with T was also analysed. Clinical characteristics and outcomes were collected. An immunohistochemistry (IHC) analysis to evaluate the altered pathway detected in preclinical models was conducted.
Results
L and T resistant clones were obtained. Protein expression underlined the activation of PI3K pathway and of its downstream effector RPS6 protein. Data obtained by microarray were analysed, identifying a large number of genes regulated by NFR2, a transcriptional regulator involved in oxidative stress, detoxification, and drug resistance. NRF2 expression was detected by WB and immunofluorescence. Cells were treated with GSK048 (G), a dual PI3K/TORCH1/2 inhibitor, showing a decrease in cell growth. siRNA of both RPS6 and NRF2 confirmed the decrease of proliferation and when treatment with antiHER2 was administered, sensitivity was restored. Interestingly after inhibiting PI3K pathway NRF2 expression decreases. In xenografts L and G were tested. G reduced both the expression of pRPS6 and NRF2. Patients with high IHC expression of pRPS6 treated with T, experienced worse outcome, suggesting that hyperactivation of the PI3K pathway may make antiHER2 treatment less effective.
Conclusions
Activation of NRF2 via PI3K seems to be consistently related to anti HER2 resistance in HER2 amplified GC.
Clinical trial identification
Legal entity responsible for the study
INCLIVA Biomedical Research Institute.
Funding
INCLIVA Biomedical Research Institute.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
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