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Simple Summary Our findings indicated that the EGF-EGFR pathway was highly activated in very young patients with recurrent or metastatic NPC. High EGFR expression in patients with metastatic NPC resulted in poor clinical outcomes. To examine whether the EGFR pathway serves as a therapeutic target for NPC, NPC patient-derived xenograft (PDX) and NPC cell lines were treated with EGFR inhibitors (EGFRi) and a cell cycle blocker. Either EGFRi or cell cycle blocker treatment alone could reduce NPC cell growth and PDX tumor growth. Furthermore, combination treatment exerted an additive suppression effect on PDX tumor growth. This study provides promising evidence that EGFRi used in combination with a cell cycle blocker may be used to treat patients with NPC. Abstract Background: Nasopharyngeal carcinoma (NPC) involves host genetics, environmental and viral factors. In clinical observations, patients of young and old ages were found to have higher recurrence and metastatic rates. Methods: Cytokine array was employed to screen druggable target(s). The candidate target(s) were confirmed through patient-derived xenografts (PDXs) and a new EBV-positive cell line, NPC-B13. Results: Overexpression of epithelial growth factor (EGF) and EGF receptor (EGFR) was detected in young patients than in older patients. The growth of NPC PDX tumors and cell lines was inhibited by EGFR inhibitors (EGFRi) cetuximab and afatinib when used separately or in combination with the cell cycle blocker palbociclib. Western blot analysis of these drug-treated PDXs demonstrated that the blockade of the EGF signaling pathway was associated with a decrease in the p-EGFR level and reduction in PDX tumor size. RNA sequencing results of PDX tumors elucidated that cell cycle-related pathways were suppressed in response to drug treatments. High EGFR expression (IHC score ≥ grade 3) was correlated with poor survival in metastatic patients (p = 0.008). Conclusions: Our results provide encouraging preliminary data related to the combination treatment of EGFRi and palbociclib in patients with NPC.