Abstract 5388
Background
EPHA2 tyrosine kinase receptor is implicated in tumor progression, stemness phenotype and resistance to treatment in a wide range of cancers. We investigated the effects of GLPG1790, a new selective Eph receptor inhibitor, in colorectal cancer (CRC) across the 4 consensus molecular subtypes (CMS).
Methods
We tested the antiproliferative effect of GLPG 1790 used alone or in combination with either 5-fluorouracil, oxaliplatin or SN38 (the active metabolite of irinotecan) in a panel of 11 CRC cell lines encompassing the 4 consensus molecular subtypes (CMS). Cell cycle analysis was performed in order to understand possible cell cycle perturbation after treatment. Pathway analysis using western blot (WB) was also performed. We then evaluated the expression of stemness genes upon treatment using qRT-PCR.
Results
GLPG 1790 is active in CRC cell lines, with the strongest activity in the cell lines from the CMS4/mesenchymal-like cluster. Combination with chemotherapeutics is not synergistic according to Chou-Talalay model. The selective inhibitor elicits a persistent inactivation of EPHA2 receptor, associated to G0-G1 cell cycle block in the sensitive cell lines. Furthermore, GLPG 1790 is able to decrease the expression of cancer stem cell genes in cell lines belonging to the CMS4 group.
Conclusions
EPHA2 blockade using the selective inhibitor GLPG 1790 has a strong antiproliferative effect in the chemorefractory subgroup of CMS4/mesenchymal-like CRC cell lines, associated to a G0-G1 cell cycle arrest.
The stronger efficacy of GLPG1790 on the mesenchymal-like subtype is probably due to the impairment of cancer cell stemness and induction of cell differentiation after treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Università della Campania "Luigi Vanvitelli"; Galapagos NV (drug supply); Associazione Italiana per la Ricerca sul Cancro (AIRC).
Disclosure
P.P. Vitiello: Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Ipsen; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Sanofi. C. Cardone: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche. D. Ciardiello: Travel/Accommodation/Expenses: Sanofi. L. Poliero: Travel/Accommodation/Expenses: BMS. C. Borrelli: Travel/Accommodation/Expenses: BMS. N. Zanaletti: Travel/Accommodation/Expenses: BMS. P. Vitale: Travel/Accommodation/Expenses: BMS. T. Troiani: Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Novartis. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Servier; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Ipsen. E. Martinelli: Honoraria (self), Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Honoraria (institution): Servier. All other authors have declared no conflicts of interest.
Resources from the same session
2791 - Efficacy of weekly paclitaxel-bevacizumab combination in advanced non squamous non-small cell lung cancer (NSCLC) : a retrospective multicentric study.
Presenter: Geoffroy Bilger
Session: Poster Display session 1
Resources:
Abstract
2916 - Post progression survival for patients treated with docetaxel/nintedanib in the SENECA trial
Presenter: Enrica Capelletto
Session: Poster Display session 1
Resources:
Abstract
1427 - Final results of randomized phase II trial of metronomic vs weekly oral vinorelbine (OV) as first-line chemotherapy (CT) in advanced NSCLC patients unfit to platinum-based CT (P-CT): Tempo-Lung EudraCT Number: 2014-003859-61
Presenter: Dariusz Kowalski
Session: Poster Display session 1
Resources:
Abstract
3789 - Pioglitazone and clarithromycin combined with metronomic low-dose chemotherapy versus nivolumab in patients with advanced non–small-cell lung cancer treated in 2nd-line and beyond: Outcomes from a randomized phase II trial (ModuLung)
Presenter: Daniel Heudobler
Session: Poster Display session 1
Resources:
Abstract
1519 - Predicting Chemotherapy Toxicity in Elderly Patients with Advanced Non-small Cell Lung Cancer: A Prospective Multicenter Study of the National Hospital Organization in Japan
Presenter: Masaki Kanazu
Session: Poster Display session 1
Resources:
Abstract
1874 - A prospective phase II trial of carboplatin (CBDCA) and nab-paclitaxel (nabPTX) for advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD)
Presenter: Toshiyuki Harada
Session: Poster Display session 1
Resources:
Abstract
3819 - Weekly Epirubicin as palliative treatment in elderly patients with malignant pleural mesothelioma.
Presenter: Paola Candido
Session: Poster Display session 1
Resources:
Abstract
3390 - Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium phase I study exploring safety and efficacy of avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates.
Presenter: Benjamin Solomon
Session: Poster Display session 1
Resources:
Abstract
5069 - Preliminary results from phase 1b study of spartalizumab plus chemotherapy for advanced non-small cell lung cancer (NSCLC)
Presenter: Armando Santoro
Session: Poster Display session 1
Resources:
Abstract
2041 - Efficacy results of selective AXL inhibitor bemcentinib with pembrolizumab following chemo in patients with NSCLC
Presenter: Jose Trigo Perez
Session: Poster Display session 1
Resources:
Abstract