Figure 3.

Main mechanism(s) of EphA2 mediated resistance to therapy. (A). EphA2-mediated activation of PI3K /AKT and MAPK mediated resistance to the EGFR blocking antibody cetuximab (and, possibly, panitumumab). (B–D) EphA2-driven activation of RSK/MTORC1/S6K1/BAD and FAK signaling mediated the resistance to anti-EGFR TKI. (E). Paclitaxel activated the Cell Adhesion Mediated-Drug Resistance (CM-DR) (mediated by mutEphB6-EphA2 interaction), through JNK/CDH11/RhoA/FAK signaling. (F). Platinum-based therapies activated EphA2-mediated EMT driven by wnt-mediated activation of Snail, Slug, and Twist. Physical and functional interaction of EphA2 and YAP has been shown to mediate platinum resistance as well. Please note that while representing independent findings, it is likely that, especially for the anti-EGFR agents (A–D), the described mechanisms may coexist, given the similarity of action between these TKIs. Please also note that for the sake of clarity, in this scheme the tumor-tissue specificity has not been considered. The description of paclitaxel- and cisplatin-EphA2 driven response has been introduced here since those therapies can be used with EGFR TKI or anti-EGFR mabs in combination settings or further lines of treatment. Thin arrows indicate direct signaling, bold arrows indicate a more complex and rather indirect involvement in the indicated biological process.