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- W4361957941 abstract "<div>AbstractPurpose:<p>Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in <i>HER2</i>-amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed.</p>Experimental Design:<p>We generated lapatinib- and trastuzumab-resistant clones deriving from two different <i>HER2</i>-amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies <i>in vitro</i> were corroborated <i>in vivo</i>. The translational relevance of our findings was verified in a patient cohort.</p>Results:<p>We found RPS6 activation and NRF2 to be related to anti-HER2 drug resistance. RPS6 or NRF2 inhibition with siRNA reduced viability and resistance to anti-HER2 drugs. In knockdown cells for RPS6, a decrease of NRF2 expression was demonstrated, suggesting a potential link between these two proteins. The use of a PI3K/TORC1/TORC2 inhibitor, tested <i>in vitro</i> and <i>in vivo</i>, inhibited pRPS6 and NRF2 expression and caused cell and tumor growth reduction, in anti–HER2-resistant models. In a cohort of <i>HER2</i>-amplified patients treated with trastuzumab and chemotherapy, a high level of NRF2 at baseline corresponds with worse progression-free survival.</p>Conclusions:<p>NRF2 through the PI3K/AKT/mTOR/RPS6 pathway could be a potential effector of resistance to anti-HER2 drugs in our models. RPS6 inhibition decreases NRF2 expression and restores sensitivity in <i>HER2</i>-amplified gastric cancer <i>in vitro</i> and <i>in vivo</i>. High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.</p></div>" @default.
- W4361957941 created "2023-04-05" @default.
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- W4361957941 date "2023-03-31" @default.
- W4361957941 modified "2023-10-17" @default.
- W4361957941 title "Data from NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in <i>HER2</i>-Amplified Gastric Cancer" @default.
- W4361957941 doi "https://doi.org/10.1158/1078-0432.c.6527910.v1" @default.
- W4361957941 hasPublicationYear "2023" @default.
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