Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

EPHA2 blockade overcomes primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC)

Date

08 Oct 2016

Session

Basic science and translational research

Presenters

Giulia Martini

Citation

Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362

Authors

G. Martini1, V. Belli2, P.P. Vitiello3, T. Troiani3, C. Cardone3, S. Napolitano3, V. Desiderio4, V. Sforza3, M.L. Ferrara3, G. Papaccio4, L. Mele4, G. Liguori5, G. Botti6, R. Franco7, F. Morgillo1, F. Ciardiello1, E. Martinelli1

Author affiliations

  • 1 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
  • 2 Dipartimento Medico-chirurgico Di Internistica Clinica E Sperimentale, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
  • 3 Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80130 - Napoli/IT
  • 4 Istology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80138 - Napoli/IT
  • 5 Anatomia Patologica, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80100 - Napoli/IT
  • 6 Dipartimento Di Anatomia Patologica, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80100 - Napoli/IT
  • 7 Anatomia Patologica, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80100 - Napoli/IT
More

Resources

Abstract 2219

Background

EPHA2 tyrosine kinase receptor is implicated in tumor progression, neovascularization and migration in a wide range of cancers. We studied its role as a potential marker of resistance to anti-EGFR drugs in colorectal cancer (CRC).

Methods

We evaluated the expression and activation of EPHA2 in a panel of CRC cell lines sensitive (GEO and SW48 cells) and resistant (HCT116, SW620, LOVO, SW480, HCT15, SW48-CR [acquired cetuximab resistant], GEO-CR) to anti-EGFR drugs by Western Blot (WB) analysis. The effect of ALW-II-41-27 (EPHA2 inhibitor) and/or cetuximab on cell survival and drug sensitivity was evaluated by MTT assay. Apoptosis and cell cycle analysis were analysed by flow cytometry. SW48-CR subcutaneous xenograft models were used for in vivo experiments. EPHA2 expression was assessed by immunohistochemistry (IHC) in mCRC tumors.

Results

EPHA2 was differently activated among cell lines with high levels of phosphorylation in HCT116, SW620, LOVO, GEO-CR and SW48-CRcells. CRC cell lines were differently sensitive to ALW-II-41-27 with an IC50 ranging from 0.05 to 2 mM (being HCT116, SW620, LOVO, SW48-CR, HCT15, GEO the most sensitive whereas GEO-CR and SW48 the most resistant). We combined ALW-II-41-27 plus cetuximab, to demonstrate if EPHA2 inhibition might revert primary and acquired resistance to cetuximab. Combined treatment induced a synergistic anti-proliferative and apoptotic effects in cells with either primary (HCT15) and acquired (GEO-CR, SW48-CR) resistance to cetuximab. The synergistic activity of the combination was confirmed by the reduction of pEPHA2 levels and a markedly inhibition of activated pMAPK and pAKT. Cell cycle analysis demonstrated G2 phase arrest with the combination compared with ALW II-41-27 alone. The in vivo experiment of SW48-CR subcutaneous xenograft models and the EPHA2 expression by IHC of mCRC tumors patients treated with anti EGFR therapy are currently ongoing and will be presented.

Conclusions

A selective EPHA2 inhibitor is able to revert in vitro primary and acquired resistance to anti-EGFR therapy, highlighting EPHA2 as a potential therapeutic target in mCRC treatment.

Clinical trial identification

Legal entity responsible for the study

Second University of Naples

Funding

AIRC

Disclosure

All authors have declared no conflicts of interest.

Resources from the same session

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings