Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in HER2-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 HER2-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 in vitro were corroborated in vivo The translational relevance of our findings was verified in a patient cohort.
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 HER2-amplified gastric cancer in vitro and in vivo High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.
http://clincancerres.aacrjournals.org/content/early/2018/11/30/1078-0432.CCR-18-2421
