Aptamer targeting EGFRvIII mutant hampers its constitutive autophosphorylation and affects migration, invasion and proliferation of glioblastoma cells
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Simona Camorani1, Elvira Crescenzi1, David Colecchia2, Andrea Carpentieri3, Angela Amoresano3, Monica Fedele1, Mario Chiariello2 and Laura Cerchia1
1 Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore” (IEOS), Consiglio Nazionale delle Ricerche (CNR), Naples, Italy
2 Istituto Toscano Tumori (ITT), Core Research Laboratory (CRL) and Consiglio Nazionale delle Ricerche (CNR), Istituto di Fisiologia Clinica (IFC), Siena, Italy
3 Dipartimento di Scienze Chimiche, Università degli Studi di Napoli “Federico II”, Naples, Italy
Laura Cerchia, email:
Keywords: aptamer, EGFRvIII, glioblastoma, PDGFRβ, combined treatment
Received: July 16, 2015 Accepted: September 23, 2015 Published: October 10, 2015
Glioblastoma Multiforme (GBM) is the most common and aggressive human brain tumor, associated with very poor survival despite surgery, radiotherapy and chemotherapy.
The epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor β (PDGFRβ) are hallmarks in GBM with driving roles in tumor progression. In approximately half of the tumors with amplified EGFR, the EGFRvIII truncated extracellular mutant is detected. EGFRvIII does not bind ligands, is highly oncogenic and its expression confers resistance to EGFR tyrosine kinase inhibitors (TKIs). It has been demonstrated that EGFRvIII-dependent cancers may escape targeted therapy by developing dependence on PDGFRβ signaling, thus providing a strong rationale for combination therapy aimed at blocking both EGFRvIII and PDGFRβsignaling.
We have recently generated two nuclease resistant RNA aptamers, CL4 and Gint4.T, as high affinity ligands and inhibitors of the human wild-type EGFR (EGFRwt) and PDGFRβ, respectively.
Herein, by different approaches, we demonstrate that CL4 aptamer binds to the EGFRvIII mutant even though it lacks most of the extracellular domain. As a consequence of binding, the aptamer inhibits EGFRvIII autophosphorylation and downstream signaling pathways, thus affecting migration, invasion and proliferation of EGFRvIII-expressing GBM cell lines.
Further, we show that targeting EGFRvIII by CL4, as well as by EGFR-TKIs, erlotinib and gefitinib, causes upregulation of PDGFRβ. Importantly, CL4 and gefitinib cooperate with the anti-PDGFRβ Gint4.T aptamer in inhibiting cell proliferation.
The proposed aptamer-based strategy could have impact on targeted molecular cancer therapies and may result in progresses against GBMs.
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