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

• Published in: Scientific reports Vol. 9; no. 1; p. 3015
• Main Authors: Valianou, Matthildi, Filippidou, Natalia, Johnson, Daniel L., Vogel, Peter, Zhang, Erik Y., Liu, Xiaolei, Lu, Yiyang, Yu, Jane J., Bissler, John J., Astrinidis, Aristotelis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-02-2019; Nature Publishing Group
• Subjects: 13/95; 38; 38/61; 59; 59/5; 631/67/1534; 631/67/327; 64/60; 82/1; 82/29; 96/106; 96/2; Anoikis; Apoptosis; Autophagy; Cell cycle; Cell growth; Cell survival; Drug resistance; Health sciences; Hospitals; Humanities and Social Sciences; Kinases; Lesions; Medicine; Mesenchyme; multidisciplinary; Mutation; Null cells; Pediatrics; Phosphorylation; Proteins; Rapamycin; Regrowth; Regulatory approval; Respiratory function; Science; Science (multidisciplinary); Tuberous sclerosis; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 2; β-Catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-39418-5

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.