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Poster display session

3891 - EPHA2 receptor is involved in in vivo acquired resistance to anti-Epidermal Growth Factor Receptor (EGFR) treatment in metastatic colorectal cancer (mCRC).

Date

11 Sep 2017

Session

Poster display session

Presenters

Giulia Martini

Citation

Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390

Authors

G. Martini1, V. Belli2, P.P. Vitiello2, T. Troiani2, C. Cardone1, S. Napolitano1, N. Matrone1, V. Sforza2, R. Franco2, F. Morgillo2, D. Ciardiello3, E. Giunta4, V. De Falco3, N. Zanaletti4, P. Vitale4, E. Martinelli3, F. Ciardiello1

Author affiliations

  • 1 Dipartimento Medico-chirurgico Di Internistica Clinica E Sperimentale "f. Magrassi E A. Lanzara", Università degli Studi della Campania "Luigi Vanvitelli", 80131 - Naples/IT
  • 2 Dipartimento Medico-chirurgico Di Internistica Clinica E Sperimentale "f. Magrassi E A. Lanzara", Università degli Studi della Campania "Luigi Vanvitelli", 80131 - naples/IT
  • 3 Oncologia Medica, Dipartimento Di Internistica Clinica E Sperimentale “f. Magrassi”,, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
  • 4 Oncologia Ed Ematologia, Università della Campania "Luigi Vanvitelli", 80131 - NAPOLI/IT
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Resources

Abstract 3891

Background

EPHA2 tyrosine kinase receptor is implicated in cell growth, migration, and invasiveness in a wide range of cancers. We studied its role as a potential marker of resistance to anti-EGFR drugs in colorectal cancer (CRC). We previously demonstrated that EPHA2 was differently activated among a panel of CRC cell lines with primary and acquired resistance to cetuximab and the use of ALW-II-41-27 (EPHA2 selective inhibitor) in combination with cetuximab was able to revert this resistance in in vitro experiments (abstract presented at 2016 ESMO Congress in Copenhagen). Here we present the study on in vivo models.

Methods

EGFR dependent SW48 and LIM1215 cell lines were engrafted into nude mice and treated with cetuximab until disease progression. Once tumors became resistant (SW48-CR and LIM1215-CR) mice were randomized in groups of 10 mice each and assigned to receive ALW- II-41-27 as single agent or in combination with cetuximab, no treatment and cetuximab alone group served as control. ALW- II-41-27 was administered daily at 30 mg/kg by oral gavage and cetuximab intraperitoneally at 1 mg/kg two days a week. Treatment was performed for three weeks, then mice were euthanized and protein expression in tumors was analysed by Western Blot.

Results

The combination of the two drugs induced a significant reduction of tumor volume since the first administration. A reduction of 50% of tumor volume was found in 5 out 10 LIM1215-CR mice treated with ALW-II-41-27 as single agent. This effect was maintained after cessation of therapy and induced prolonged survival. Tumor protein analysis by WB demonstrated a strong reduction of EPHA2 expression and activation in mice treated with the combination of ALW-II-41-27 and cetuximab, accompanied by a significantly inhibition of activated pMAPK and pAKT.

Conclusions

These results highlight the role of EPHA2 as a potential therapeutic target in mCRC treatment.

Clinical trial identification

Legal entity responsible for the study

Università della Campania Luigi Vanvitelli

Funding

None

Disclosure

All authors have declared no conflicts of interest.

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