RT Journal Article
T1 The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells
A1 Muñoz-Guardiola, Pau
A1 Casas, Josefina
A1 Megías-Roda, Elisabet
A1 Solé, Sònia
A1 Perez-Montoyo, Héctor
A1 Yeste-Velasco, Marc
A1 Erazo, Tatiana
A1 Diéguez-Martínez, Nora
A1 Espinosa-Gil, Sergio
A1 Muñoz-Pinedo, Cristina
A1 Yoldi, Guillermo
A1 Abad, José Luis
A1 Segura, Miguel
A1 Morán, Teresa
A1 Romeo, Margarita
A1 Bosch-Barrera, Joaquim
A1 Oaknin, Ana
A1 Alfón, José
A1 Domènech, Carles
A1 Fabriàs, Gemma
A1 Velasco Díez, Guillermo
A1 Lizcano, Jose Miguel
AB ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.
PB Taylor & Francis
SN 1554-8627
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/101086
UL https://hdl.handle.net/20.500.14352/101086
LA eng
NO Pau Muñoz-Guardiola, Josefina Casas, Elisabet Megías-Roda, Sònia Solé, Héctor Perez-Montoyo, Marc Yeste-Velasco, Tatiana Erazo, Nora Diéguez-Martínez, Sergio Espinosa-Gil, Cristina Muñoz-Pinedo, Guillermo Yoldi, Jose L Abad, Miguel F Segura, Teresa Moran, Margarita Romeo, Joaquim Bosch-Barrera, Ana Oaknin, Jose Alfón, Carles Domènech, Gemma Fabriàs, Guillermo Velasco & Jose M Lizcano (2021) The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells, Autophagy, 17:6, 1349-1366, DOI: 10.1080/15548627.2020.1761651
NO This work was supported by the Centre for Industrial Technological Development [CDTI,INNOGLOBAL/20171061]; European Regional Development Fund [PI18/00442 and PI15/00339]; [INNPACTO/IPT-2012-0614-010000, RETOS RTC2017-6261-1, SAF2015-64237-R]; Fundació la Marató de TV3 [20134031]; H2020 Marie Skłodowska-Curie Actions [TRAIN GA721532]; Instituto de Salud Carlos III [PI15/00339]; [PI18/00442]; Ministerio de Ciencia, Innovación y Universidades [CTQ2017- 85378-R]; Ministerio de Economía y Competitividad [RTC-2015-3821-1]; [RTC-2017-6261-1];  [EMP-TU-2015-4576]; [RETOS RTC-2017-6261-1];  [BFU2016-78154-R]; [INNPACTO/IPT-2012-0614-010000]; [SAF2015-64237-R];  [RTC-2014-1532-1].
NO European Commission
NO Fundació la Marató de TV3
NO Instituto de Salud Carlos III
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 9 abr 2025