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• W2891753260 abstract "Background: Molecular mechanisms responsible for resistance to targeted agents are no longer clear and need to be clarified. Many pathways have been stressed to be responsible for acquired resistance in HER2 amplified GC, among them, PI3K/AKT/mTOR plays a relevant role. NRF2 was recently identified as a possible mechanism implicated in resistance to chemotherapy. Methods: OE19 and NCIN87, HER2+ GC cell lines were treated with increasing doses of Lapatinib (L) and Trastuzumab (T) to obtain resistant clones. These were isolated and characterized by performing mutational analysis and protein expression by Western blot (WB). Genome expression profile was done by ClariomS microarray. Inhibition of the altered pathways was evaluated using a panel of selected drugs. siRNAs were performed to characterise the role of the inhibition of selected proteins. An in vivo experiment was conducted to corroborate results. A retrospective cohort of HER2 amplified patients treated with T was analysed. An immunohistochemistry (IHC) analysis to evaluate the altered pathway detected in preclinical models was conducted. Results: L and T resistant clones were obtained. In resistant cells, protein expression underlined the activation of PI3K pathway and of its downstream effector RPS6 protein. Analysing microarray, it was possible to identify, the activation of a large number of genes regulated by NFR2. Its expression was confirmed by WB; NRF2 nuclear activation was detected by nuclear fractionating WB and immunofluorescence. A panel of target agents was used to evaluate NRF2 changes. It was possible to observe the its expression strongly decrease by using PI3K pathway inhibitors, suggesting a relation between this pathway and NRF2. To better clarify this phenomenon, siRNA of RPS6, that was detected to be activated in resistant cells, was performed and it was possible to observe a strong decrease of NRF2 expression and sensitivity to antiHER2 drugs was restored. IHC of both RPS6 and NRF2 were performed suggesting that the activation of both RPS6 and NRF2 related with less clinical benefit of T. Conclusions: RPS6 through the activation of NRF2 should be considered a new mechanism responsible for antiHER2 drugs resistance in GC. Further investigations are needed. Legal entity responsible for the study: INCLIVA Biomedical Research Institute. Funding: INCLIVA Biomedical Research Institute. Disclosure: All authors have declared no conflicts of interest." @default.
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• W2891753260 date "2018-09-01" @default.
• W2891753260 modified "2023-10-17" @default.
• W2891753260 title "RPS6 through the activation of NRF2 causes resistance to antiHER2 drugs in HER2 amplified gastric cancer (GC) models" @default.
• W2891753260 doi "https://doi.org/10.1093/annonc/mdy314.039" @default.
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