Overcoming AZD9291 Resistance and Metastasis of NSCLC via Ferroptosis and Multitarget Interference by Nanocatalytic Sensitizer Plus AHP-DRI-12.

The acquired resistance to Osimertinib (AZD9291) greatly limits the clinical benefit of patients with non-small cell lung cancer (NSCLC), whereas AZD9291-resistant NSCLCs are prone to metastasis. It's challenging to overcome AZD9291 resistance and suppress metastasis of NSCLC simultaneously. Here, a nanocatalytic sensitizer (VF/S/A@CaP) is proposed to deliver Vitamin c (Vc)-Fe(II), si-OTUB2, ASO-MALAT1, resulting in efficient inhibition of tumor growth and metastasis of NSCLC by synergizing with AHP-DRI-12, an anti-hematogenous metastasis inhibitor by blocking the amyloid precursor protein (APP)/death receptor 6 (DR6) interaction designed by our lab. Fe released from Vc-Fe(II) generates cytotoxic hydroxyl radicals (•OH) through Fenton reaction. Subsequently, glutathione peroxidase 4 (GPX4) is consumed to sensitize AZD9291-resistant NSCLCs with high mesenchymal state to ferroptosis due to the glutathione (GSH) depletion caused by Vc/dehydroascorbic acid (DHA) conversion. By screening NSCLC patients' samples, metastasis-related targets (OTUB2, LncRNA MALAT1) are confirmed. Accordingly, the dual-target knockdown plus AHP-DRI-12 significantly suppresses the metastasis of AZD9291-resistant NSCLC. Such modality leads to 91.39% tumor inhibition rate in patient-derived xenograft (PDX) models. Collectively, this study highlights the vulnerability to ferroptosis of AZD9291-resistant tumors and confirms the potential of this nanocatalytic-medicine-based modality to overcome critical AZD9291 resistance and inhibit metastasis of NSCLC simultaneously.