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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

5695 - Potential role of RICTOR copy number gain (CNG) as a key biomarker of mTOR activity: A comprehensive preclinical analysis in Squamous Cell Lung Cancer (SQLC) models.

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Anastasios Gkountakos

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

A. Gkountakos1, S. Pilotto2, M. Simbolo3, C. Vicentini3, A. Mafficini1, A. del Curatolo1, A. Scarpa4, G. Tortora2, V. Corbo3, E. Bria5

Author affiliations

  • 1 Department Of Diagnostics And Public Health, Section Of Anatomical Pathology, University and Hospital Trust of Verona, 37134 - Verona/IT
  • 2 Medical Oncology, University of Verona, AOUI Verona, 37134 - Verona/IT
  • 3 Department Of Diagnostics And Public Health, Section Of Anatomical Pathology, University and Hospital Trust of Verona, Verona/IT
  • 4 Arc-net Research Centre And Department Of Diagnostics And Public Health - Sectio, AOU Integrata Verona "Borgo Roma", 37134 - Verona/IT
  • 5 Uoc Oncologia Medica, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario Agostino Gemelli, 00168 - Rome/IT
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Resources

Abstract 5695

Background

We previously performed a multi-step genomic study in almost 100 resected SQLC patients dichotomized according to the prognosis. Among the pathways with a biological impact on SQLC oncogenesis, PI3K/mTOR-Rictor emerged as a crucial axis [Pilotto WCLC 2016]. In order to explore the potentiality of mTOR inhibition, we present a set of in vitro experiments in RICTOR-aberrant SQLC preclinical models.

Methods

Next-generation sequencing (NGS), fluorescence in situ hybridization (FISH) and Western Blot were performed in 3 SQLC cell lines (H-1703, SK-Mes-1, Calu-1) for detecting CNG/protein profile of the PI3K/mTOR-Rictor components. The activity of PI3K/mTOR pathway targeted inhibitors in the SQLC cell lines was examined in short- (72 hours) and long-term (1 week) cell viability assays.

Results

NGS analysis revealed a different amount of RICTOR CNG among SQLC cell lines. FISH confirmed that H-1703 harbors the highest number of RICTOR copies (6) followed by SK-Mes-1 (4) and Calu-1 (3.5), suggesting polysomy of the short arm of chromosome 5 as the main mechanism of RICTOR gain. Although Rictor protein levels were similar among the cell lines, p-mTOR S2448 (active form of mTOR complexes) was higher in H-1703 than SK-Mes-1 and Calu-1. PI3K/mTOR inhibition proved more effective in H-1703, with lower IC50 values in short term treatment (Table). Similar findings were confirmed in long-term assays.Table: 1879P

DrugsH-1703Calu-1SK-Mes-1
IC50 (nM)
PF-05212384 (PI3K/mTOR inhibitor)1826335
AZD-2014 (Dual mTORC1/C2 inhibitor)145217215
Everolimus (mTORC1 inhibitor)Unable determine IC50Unable determine IC50Unable determine IC50
MK-2206 (pan-Akt inhibitor)Unable determine IC50Unable determine IC50Unable determine IC50

Conclusions

Overall, the results of our study suggest the potential implication of PI3K/mTOR-Rictor pathway in SQLC oncogenesis, thus rendering it a promising target for a targeted approach. Among the mTOR components, RICTOR CNG seems to predict a higher sensitivity to PI3K/mTOR inhibition and might represent a potential biomarker to be explored as a stratification tool in clinical trials. Confirmatory RICTOR silencing experiments are currently ongoing.

Clinical trial identification

Legal entity responsible for the study

Emilio Bria.

Funding

AIRC (Associazione Italiana per la Ricerca sul Cancro).

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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