2. Academic Validation
  3. Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance

Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance

  • J Hematol Oncol. 2018 Aug 29;11(1):109. doi: 10.1186/s13045-018-0651-z.
Zhentao Liu 1,  Zuhua Chen 1,  Jingyuan Wang 1,  Mengqi Zhang 1,  Zhongwu Li 2,  Shubin Wang 3,  Bin Dong 2,  Cheng Zhang 1,  Jing Gao 4 5,  Lin Shen 6 7
Affiliations

Affiliations

  • 1 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
  • 3 Department of Oncology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, China.
  • 4 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China. gaojing_pumc@163.com.
  • 5 Department of Oncology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, China. gaojing_pumc@163.com.
  • 6 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China. shenlin@bjmu.edu.cn.
  • 7 Department of Oncology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518036, Guangdong, China. shenlin@bjmu.edu.cn.
PMID: 30157900 DOI: 10.1186/s13045-018-0651-z
Abstract

Background: No approved targeted agents are available for esophageal squamous cell carcinoma (ESCC). Informative genomic analysis and mouse patient-derived xenografts (PDX) also called mouse avatar can greatly expedite drug discovery.

Methods: Six ESCC cell lines and 7 out of 25 PDX models derived from 188 biopsies with clear molecular features were employed to evaluate the sensitivity of several EGFR blockers in vitro and in vivo, as well as the underlying antitumor mechanisms of the most promising EGFR-TKI afatinib. Mechanisms involved in acquired resistance of afatinib were explored based on established resistant cell lines and PDX models followed by an attempt to reverse resistance.

Results: Compared with Other EGFR blockers, the second-generation EGFR-TKI afatinib exerted superior antitumor effects in ESCC, and EGFR copy number gain (CNG) or overexpression was proposed to be predictive biomarkers. Afatinib played its antitumor effects by inhibiting EGFR downstream pathways, as well as inducing Apoptosis and cell cycle arrest at G1. It was increased phosphorylation of Src family kinases (SFKs), rather than MET upregulation, that conferred to acquired resistance of afatinib. Dual blockade of EGFR and SFKs could overcome afatinib resistance and warrants validation in clinical practice.

Conclusion: Both ESCC cell lines and PDXs with EGFR CNG or overexpression are potential candidates for afatinib, and concomitant EGFR/SFKs inhibition could reverse afatinib-acquired resistance caused by SFKs activation in ESCC.

Keywords

Acquired resistance; Afatinib; ESCC; Mouse avatar; Src family kinases.

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