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Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Matthildi Valianou1,2, Natalia Filippidou1,2, Daniel L Johnson3

  • 1Division of Pediatric Nephrology, Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, 38103, USA.

Scientific Reports
|March 1, 2019
PubMed

Insights

Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) treatments face resistance due to cell reprogramming. Understanding these changes is key to developing therapies for long-term remission in TSC and LAM patients.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) stem from TSC1/TSC2 mutations, causing mTORC1 overactivation.
  • Rapalogs, mTORC1 inhibitors, treat TSC and LAM but are cytostatic, necessitating lifelong use and risking drug resistance.
  • Acquired resistance to rapalogs is a significant clinical challenge, driving the need to understand resistance mechanisms.

Purpose of the Study:

  • To investigate the signaling pathways and cellular changes that lead to acquired resistance to rapalogs in TSC and LAM.
  • To develop a cellular model for studying rapalog resistance in Tuberous Sclerosis Complex.

Main Methods:

  • Development of the first Tsc2-null rapamycin-resistant cell line (ELT3-245) from a Tuberous Sclerosis Complex model.
  • In vitro characterization of ELT3-245 cells for anchorage-independent survival, anoikis resistance, and epithelial marker expression.
  • Analysis of key signaling alterations, including β-catenin pathway activation, in resistant cells.

Main Results:

  • The ELT3-245 cell line demonstrated high tumorigenicity in mice and resistance to rapamycin.
  • ELT3-245 cells exhibited increased survival independent of anchorage and resistance to programmed cell death (anoikis).
  • A significant increase in β-catenin signaling was observed in the resistant cell line, alongside a loss of epithelial markers.

Conclusions:

  • Rapamycin-resistant cells may arise from pre-existing signaling aberrations or reprogramming of Tsc2-null cells towards a mesenchymal-like phenotype.
  • Increased β-catenin signaling and mesenchymal transition are potential mechanisms underlying rapalog resistance in TSC and LAM.
  • Targeting these acquired signaling changes could lead to improved therapeutic strategies for achieving long-term remissions in TSC and LAM.

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