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

Matthildi Valianou, Natalia Filippidou, Daniel L. Johnson, Peter Vogel, Erik Y. Zhang, Xiaolei Liu, Yiyang Lu, Jane J. Yu, John Bissler, Aristotelis Astreinidis

Research output: Contribution to journalArticle

Abstract

Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased β-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TSC-null cells are reprogrammed to express mesenchymal-like markers. These signaling changes could be further exploited to induce clinically-relevant long-term remissions.

Original languageEnglish (US)
Article number3015
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Null Lymphocytes
Sirolimus
Tuberous Sclerosis
Lymphangioleiomyomatosis
Anoikis
Catenins
Cytostatic Agents
Drug Resistance
Cell Survival
Cell Line
Lung
Mutation

All Science Journal Classification (ASJC) codes

  • General

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Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells. / Valianou, Matthildi; Filippidou, Natalia; Johnson, Daniel L.; Vogel, Peter; Zhang, Erik Y.; Liu, Xiaolei; Lu, Yiyang; Yu, Jane J.; Bissler, John; Astreinidis, Aristotelis.

In: Scientific reports, Vol. 9, No. 1, 3015, 01.12.2019.

Research output: Contribution to journalArticle

Valianou, M, Filippidou, N, Johnson, DL, Vogel, P, Zhang, EY, Liu, X, Lu, Y, Yu, JJ, Bissler, J & Astreinidis, A 2019, 'Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells', Scientific reports, vol. 9, no. 1, 3015. https://doi.org/10.1038/s41598-019-39418-5
Valianou M, Filippidou N, Johnson DL, Vogel P, Zhang EY, Liu X et al. Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells. Scientific reports. 2019 Dec 1;9(1). 3015. https://doi.org/10.1038/s41598-019-39418-5
Valianou, Matthildi ; Filippidou, Natalia ; Johnson, Daniel L. ; Vogel, Peter ; Zhang, Erik Y. ; Liu, Xiaolei ; Lu, Yiyang ; Yu, Jane J. ; Bissler, John ; Astreinidis, Aristotelis. / Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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