Combination of Epithelial Growth Factor Receptor Blockers and CDK4/6 Inhibitor for Nasopharyngeal Carcinoma Treatment.

Hsin‐Pai Li ,Hung-Ming Wang,An-Chi Lin,Yuan-Ming Yeh,Hsien-Chi Fan,Kai‐Ping Chang ,Yin‐Kai Chao ,Tsan-Shiun Lin ,Jason Chia‐Hsun Hsieh ,Yung‐Chia Kuo ,Kar‐Wai Lui ,Yi‐Ting Lai ,Minghui Huang ,Chun‐Nan Yeh ,Li‐Yu Lee ,Yu‐Sun Chang ,Yen‐Lin Huang ,Chien‐Tai Lin ,Chenyang Huang ,Cheng‐Lung Hsu

doi:10.3390/cancers13122954

Hsin‐Pai Li , Hung-Ming Wang + Show 18 more

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https://doi.org/10.3390/cancers13122954

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Journal: Cancers	Publication Date: Jun 12, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Chang Gung University, Chang Gung Memorial Hospital

Abstract

Simple SummaryOur 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.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.

Highlights

Nasopharyngeal carcinoma (NPC) is a prevalent head and neck tumor in SoutheastAsia, including Taiwan [1]
Transcriptomic, bioinformatic, and omics studies have indicated that aberrant signal transduction pathways including epithelial growth factor (EGF) receptor (EGFR), nuclear factor kappa-B (NF-κB) [11], WNT/β-catenin [12], PI3K/Akt/mTOR, p53, PARP, MAPK, STAT, cell cycle pathways, and miRNAs/lncRNAs [13,14] may result in tumor progression and treatment resistance in NPC
A cell cycle-dependent kinase CDK4/6 inhibitor, palbociclib (PAL), was selected in the current study because we previously reported that this cell cycle inhibitor could suppress NPC tumor growth in an NPC patient-derived xenografts (PDXs) animal model [21]

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a prevalent head and neck tumor in SoutheastAsia, including Taiwan [1]. Inhibitors including the EGFR monoclonal antibody and tyrosine kinase inhibitors [20] that block EGF-EGFR signaling and a cell cycle blocker could impede tumor growth. To test this hypothesis, EGF-EGFR inhibitors and/or cell cycle blockers were used to inhibit NPC growth in our NPC patient-derived xenograft (PDX) mouse model [21] and a recently established NPC PDX-derived cell line. Drug tests in NPC PDX animal models and RNA-seq data may reveal that EGF signaling and cell cycle inhibitors effectively suppressed NPC tumor growth.

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