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Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Núria Eritja1,2, Bo-Juen Chen3, Ruth Rodríguez-Barrueco4

  • 1a Department of Basic Sciences , Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.4 , Lleida , Spain.

Autophagy
|January 6, 2017
PubMed

Insights

Sorafenib resistance in endometrial cancer (EC) is linked to protective autophagy. Targeting autophagy enhances drug effectiveness and reduces tumor growth and metastasis in EC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted therapies, including kinase inhibitors, often fail to achieve complete remission in endometrial cancer (EC), leading to relapse due to drug resistance.
  • Sorafenib, a multi-kinase inhibitor, has shown limited efficacy in advanced uterine carcinoma, necessitating an understanding of its resistance mechanisms.
  • Identifying adaptive mechanisms is crucial for overcoming clinical drug resistance and improving targeted therapy outcomes in EC.

Purpose of the Study:

  • To investigate the mechanisms underlying sorafenib resistance in endometrial cancer.
  • To explore the role of the lysosomal pathway and autophagy in EC's adaptive response to sorafenib.
  • To evaluate the therapeutic potential of targeting autophagy to enhance sorafenib efficacy in EC.

Main Methods:

  • Utilized RNA-sequencing data from the Cancer Cell Line Encyclopedia and high-throughput screening data.
  • Conducted functional biology studies to assess the role of autophagy in sorafenib resistance.
  • Performed in vivo experiments, including subcutaneous tumor models, lung metastasis assays, and orthoxenografts, to evaluate therapeutic strategies.

Main Results:

  • Identified the lysosomal pathway and macroautophagy/autophagy as key components of sorafenib resistance in EC.
  • Demonstrated that sorafenib induces a protective, MAPK/JNK-dependent autophagic response in EC cells.
  • Showed that inhibiting autophagy significantly enhances sorafenib-induced cytotoxicity, suppresses tumor growth, and reduces pulmonary metastasis.

Conclusions:

  • Sorafenib treatment activates a protective autophagic response in endometrial cancer cells, contributing to therapeutic resistance.
  • Targeting autophagy in combination with sorafenib presents a promising therapeutic strategy to overcome resistance and improve treatment outcomes in advanced or recurrent EC.
  • These findings offer critical insights into the resistance mechanisms of advanced EC and propose a novel approach for therapeutic intervention.
Keywords:
MAPK/JNKPDXautophagyendometrial cancerkinaselysosomessorafenibtargeted therapy

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