Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo.

El Mokh, Oussama; Ruffieux-Daidié, Dorothée; Rölli, Matthias Andreas; Stooss, Amandine; Phillips, Wayne A; Gertsch, Jürg; Dettmer, Matthias; Charles, Roch-Philippe (2017). Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. OncoTarget, 8(15), pp. 24604-24620. Impact Journals LLC 10.18632/oncotarget.15599

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Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3'-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi'3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3'-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction.In conclusion, combination therapy of MEK and Pi3'-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
09 Interdisciplinary Units > Microscopy Imaging Center MIC

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

El Mokh, Oussama; Rölli, Matthias Andreas; Stooss, Amandine; Gertsch, Jürg; Dettmer, Matthias and Charles, Roch-Philippe

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Language:

English

Submitter:

Matthias Dettmer

Date Deposited:

15 Dec 2017 09:56

Last Modified:

23 Oct 2019 01:22

Publisher DOI:

10.18632/oncotarget.15599

PubMed ID:

28445948

Uncontrolled Keywords:

BRAF Pi3K combination treatment genetically engineered mice thyroid cancer

BORIS DOI:

10.7892/boris.107143

URI:

https://boris.unibe.ch/id/eprint/107143

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