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Shp2 regulates migratory behavior and response to EGFR-TKIs through ERK1/2 pathway activation in non-small cell lung

Yu-Jing Sun1,2, Zhong-Ling Zhuo1, Hai-Peng Xian1

  • 1Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China.

Oncotarget
|December 7, 2017
PubMed

Insights

The tyrosine phosphatase Shp2 is overexpressed in non-small cell lung cancer (NSCLC), promoting metastasis and drug resistance. Inhibiting Shp2 may enhance treatment efficacy for NSCLC patients, particularly those with EGFR mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Therapy failure in non-small cell lung cancer (NSCLC) is often due to metastasis and drug resistance.
  • The role of tyrosine phosphatase Shp2 in NSCLC progression, metastasis, and drug resistance remains to be fully elucidated.

Purpose of the Study:

  • To investigate the involvement of Shp2 in the development of metastasis and drug resistance in NSCLC.
  • To explore the potential of targeting Shp2 as a therapeutic strategy for NSCLC.

Main Methods:

  • Shp2 expression analysis in clinical NSCLC samples.
  • Shp2 knockdown and overexpression experiments in NSCLC cell lines.
  • Assessment of cell proliferation, migration, and expression of key proteins (c-Myc, fibronectin, E-cadherin).
  • Evaluation of cellular sensitivity to gefitinib in EGFR-mutated and wild-type NSCLC cells.
  • Investigation of the role of the ERK1/2 pathway in Shp2-mediated effects.

Main Results:

  • Shp2 was found to be overexpressed in a subset of NSCLC tissues.
  • Shp2 knockdown inhibited NSCLC cell proliferation and migration, reduced c-Myc and fibronectin, and increased E-cadherin.
  • Shp2 knockdown sensitized EGFR-mutated NSCLC cells to gefitinib, while Shp2 overexpression induced resistance in wild-type EGFR cells.
  • Shp2 activated the ERK1/2 pathway, leading to decreased E-cadherin and increased fibronectin and c-Myc expression.

Conclusions:

  • Shp2 plays a significant role in promoting NSCLC proliferation, migration, and resistance to EGFR tyrosine kinase inhibitors (TKIs).
  • Co-inhibition of EGFR and Shp2 presents a promising strategy to overcome acquired resistance to gefitinib in NSCLC with EGFR T790M mutations.
  • Shp2 could serve as a novel biomarker for NSCLC treatment strategies.
Keywords:
ERK1/2Shp2epidermal growth factor receptornon-small cell lung cancertyrosine kinase inhibitors

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