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Molecular Characteristics of Everolimus-resistant Renal Cell Carcinoma Cells Generated by Continuous Exposure to

Yuko Nakayama1, Daichi Enomoto2, Kazuhiro Yamamoto3

  • 1Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.

Anticancer Research
|September 29, 2023
PubMed
Abstract

Insights

Developing everolimus-resistant renal cell carcinoma (RCC) cells revealed cross-resistance to mTOR inhibitors. This resistance was linked to decreased mTOR activity and specific gene expression changes, offering insights into treatment challenges.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin (mTOR) inhibitors are standard treatment for metastatic renal cell carcinoma (RCC).
  • Poor treatment outcomes suggest potential issues with mTOR inhibitor tolerability.
  • Understanding resistance mechanisms is crucial for improving RCC therapy.

Purpose of the Study:

  • To establish everolimus-resistant renal cell carcinoma (RCC) sublines.
  • To compare the molecular characteristics of these resistant sublines with their parental counterparts.
  • To investigate potential mechanisms underlying everolimus resistance in RCC.

Main Methods:

  • Human RCC cell lines (Caki-2 and 786-O) were continuously exposed to everolimus.
  • Established resistant sublines (Caki/EV and 786/EV) were characterized.
  • Comparative analysis of cellular sensitivity, mTOR signaling, and gene expression profiles was performed.

Main Results:

  • Resistant sublines (Caki/EV, 786/EV) exhibited cross-resistance to other mTOR inhibitors.
  • While mTOR and effector expression remained unchanged, mTOR activity (S6K phosphorylation) decreased in resistant cells.
  • Specific gene expression alterations were observed, including increased INSR, TP53, IGFBP3 in Caki/EV and TELO2, HRAS, SGK1 in 786/EV, alongside decreased DDIT4, DEPTOR, HIF1A, and PLD1 in both.

Conclusions:

  • Novel everolimus-resistant RCC sublines demonstrate cross-resistance to mTOR inhibitors.
  • Reduced mTOR activity and specific gene expression changes, particularly down-regulation of DDIT4, DEPTOR, HIF1A, and PLD1, may drive resistance.
  • These findings provide molecular insights into everolimus resistance mechanisms in renal cell carcinoma.
Keywords:
EverolimusmTORmultidrug resistancerenal cell carcinoma

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