NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in <i>HER2</i>-Amplified Gastric Cancer.

Abstract

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. 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. 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. 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.