TY - JOUR
T1 - High-throughput screening uncovers miRNAs enhancing glioblastoma cell susceptibility to tyrosine kinase inhibitors
AU - Cunha, Pedro P.
AU - Costa, Pedro M.
AU - Morais, Catarina M.
AU - Lopes, Inês R.
AU - Cardoso, Ana M.
AU - Cardoso, Ana L.
AU - Mano, Miguel
AU - Jurado, Amália S.
AU - Pedroso De Lima, Maria C.Pedroso
N1 - Funding Information:
This work was supported by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0145-FEDER-000008: BrainHealth 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundac¸ão para a Ciência e a Tecnologia, I.P., under projects POCI-01-0145-FEDER-016390: CANCEL STEM and POCI-01-0145-FEDER-007440. This work was also supported by the Italian Ministry of Education and the FCT Investigator Programme [IF/00694/2013 to M.M]. A.M.C. and A.L.C. are recipients of fellowships from the FCT with references SFRH/ BPD/99613/2014 and SFRH/BPD/108312/2015, respectively.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - Glioblastoma (GBM) is a deadly and therapy resistant malignant brain tumour, characterized by an aggressive and diffuse growth pattern, which prevents complete surgical resection. Despite advances in the identification of genomic and molecular alterations that fuel the tumour, average patient survival post-diagnosis remains very low (~14.6-months). In addition to being highly heterogeneous, GBM tumour cells exhibit high adaptive capacity to targeted molecular therapies owing to an established network of signalling cascades with functional redundancy, which provides them with robust compensatory survival mechanisms. Here, we investigated whether a multimodal strategy combining multitargeted tyrosine kinase inhibitors (MTKIs) and microRNA (miRNA) modulation could overcome the signalling pathway redundancy in GBM and, hence, promote tumour cell death. By performing a high-throughput screening, we identified a myriad of miRNAs, including those belonging to the miR-302-3p/372-3p/373-3p/520-3p family, which coordinately act with the MTKI sunitinib to decrease GBM cell viability. Two members of this family, hsa-miRNA-302a-3p and hsa-miRNA-520 b, were found to modulate the expression of receptor tyrosine kinase mediators (including AKT1, PIK3CA and SOS1) in U87 and DBTRG human GBM cells. Importantly, administration of mimics of these miRNAs with sunitinib or axitinib resulted in decreased tumour cell proliferation and enhanced cell death, whereas no significant effect was observed when coupling miRNA modulation with temozolomide, the first-line drug for GBM therapy. Overall, our results provide evidence that combining the 'horizontal' inhibition of signalling pathways promoted by MTKIs with the 'vertical' inhibition of the downstreamsignalling cascade promoted by hsa-miR-302a-3p and hsamiR- 520 b constitutes a promising approach towards GBM treatment.
AB - Glioblastoma (GBM) is a deadly and therapy resistant malignant brain tumour, characterized by an aggressive and diffuse growth pattern, which prevents complete surgical resection. Despite advances in the identification of genomic and molecular alterations that fuel the tumour, average patient survival post-diagnosis remains very low (~14.6-months). In addition to being highly heterogeneous, GBM tumour cells exhibit high adaptive capacity to targeted molecular therapies owing to an established network of signalling cascades with functional redundancy, which provides them with robust compensatory survival mechanisms. Here, we investigated whether a multimodal strategy combining multitargeted tyrosine kinase inhibitors (MTKIs) and microRNA (miRNA) modulation could overcome the signalling pathway redundancy in GBM and, hence, promote tumour cell death. By performing a high-throughput screening, we identified a myriad of miRNAs, including those belonging to the miR-302-3p/372-3p/373-3p/520-3p family, which coordinately act with the MTKI sunitinib to decrease GBM cell viability. Two members of this family, hsa-miRNA-302a-3p and hsa-miRNA-520 b, were found to modulate the expression of receptor tyrosine kinase mediators (including AKT1, PIK3CA and SOS1) in U87 and DBTRG human GBM cells. Importantly, administration of mimics of these miRNAs with sunitinib or axitinib resulted in decreased tumour cell proliferation and enhanced cell death, whereas no significant effect was observed when coupling miRNA modulation with temozolomide, the first-line drug for GBM therapy. Overall, our results provide evidence that combining the 'horizontal' inhibition of signalling pathways promoted by MTKIs with the 'vertical' inhibition of the downstreamsignalling cascade promoted by hsa-miR-302a-3p and hsamiR- 520 b constitutes a promising approach towards GBM treatment.
UR - http://www.scopus.com/inward/record.url?scp=85034256071&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddx323
DO - 10.1093/hmg/ddx323
M3 - Article
C2 - 28973155
AN - SCOPUS:85034256071
SN - 0964-6906
VL - 26
SP - 4375
EP - 4387
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -