Herein, we have generated a nuclease-resistant RNA-aptamer (named CL4) able to bind at high affinity to EGFR on the surface of different cancer cells and to block EGFR downstream signaling via inhibition of either EGFR homodimers and heterodimers with cognate ErbB2 or ErbB3, thus irrespective of the ligand that causes receptors dimerization. The gene discussed is ERBB2; the disease is cancer.