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Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an omic approach to identify novel druggable targets

Authors Ravegnini G, Sammarini G, Moran S, Calice G, Indio V, Urbini M, Astolfi A, Zanotti F, Pantaleo MA, Hrelia P, Angelini S

Received 30 December 2018

Accepted for publication 16 April 2019

Published 5 July 2019 Volume 2019:11 Pages 6229—6244


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Antonella D'Anneo

Gloria Ravegnini,1,* Giulia Sammarini,1,* Sebastian Moran,2 Giovanni Calice,3 Valentina Indio,4 Milena Urbini,4 Annalisa Astolfi,4 Federica Zanotti,1 Maria A Pantaleo,4,5 Patrizia Hrelia,1 Sabrina Angelini1

1Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; 2Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institue (Idibell), l’Hospitalet de Llobregat, Barcelona, Spain; 3Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy; 4Giorgio Prodi Cancer Research Center, University of Bologna, Bologna, Italy; 5Department of Specialized, Experimental, and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

*These authors contributed equally to this work

Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance.
Methods: For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells.
Results: We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism.
Conclusion: Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.

Keywords: gastrointestinal stromal tumors, GIST, BYL719, PI3K inhibitor, tyrosine-kinase inhibitors

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