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GATA6-upregulating autophagy promotes TKI resistance in nonsmall cell lung cancer

Ruishuang Ma1, Xin Li1, Huan Liu2

  • 1Department of Internal Medical Oncology, Harbin medical University Cancer Hospital , Harbin , Heilongjiang Province , China.

Cancer Biology & Therapy
|May 17, 2019
PubMed

Insights

GATA6 enhances autophagy, contributing to tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). Targeting GATA6 and autophagy may overcome drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Autophagy's role in cancer and drug resistance is complex and not fully understood.
  • Investigating autophagy mechanisms in lung cancer is crucial for developing effective treatments.

Purpose of the Study:

  • To evaluate autophagy activity in lung cancer cells with varying origins.
  • To explore the regulatory mechanisms of autophagy in tyrosine kinase inhibitor (TKI) resistance.
  • To identify potential therapeutic targets for overcoming drug resistance in non-small cell lung cancer (NSCLC).

Main Methods:

  • Comparing basal and erlotinib-induced autophagy in sensitive and resistant lung cancer cell lines.
  • Assessing the impact of autophagy inhibition (3-MA) on apoptosis and cell viability.
  • Analyzing GATA6 expression and its effect on autophagy and cell viability.
  • Immunohistochemical staining of GATA6 and LC3-II in NSCLC patient tissues.
  • Statistical analysis including chi-square tests and Kaplan-Meier survival analysis.

Main Results:

  • Resistant cells showed no significant basal autophagy increase, but H1650 cells exhibited a threefold increase after erlotinib treatment.
  • Inhibiting autophagy increased apoptosis in H1650 cells, while H1650 cells showed more autophagosomes compared to PC9 cells.
  • GATA6 expression was elevated in resistant cells post-erlotinib; its knockdown reduced autophagy and cell viability.
  • GATA6 and LC3-II were significantly increased in insensitive NSCLC tissues, correlating positively with each other.
  • High GATA6 expression was associated with lower overall and progression-free survival rates in NSCLC patients treated with EGFR-TKI.

Conclusions:

  • GATA6 promotes autophagy activity, contributing to TKI resistance in NSCLC.
  • Targeting GATA6 and autophagy concurrently with TKIs presents a promising strategy to overcome drug resistance in NSCLC.
  • GATA6 serves as a potential biomarker for predicting TKI treatment outcomes in NSCLC.
Keywords:
Exon 19 deletionsGATA6Non-small cell lung cancerTKI resistanceautophagy

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