Paradoxical Activation of c-Src as a Drug-Resistant Mechanism

ATP-competitive inhibitors have been developed as promising anti-cancer agents. However, drug-resistance frequently occurs and the mechanisms underlying drug-resistance are not fully understood. Here we show that paradoxical activation of c-Src occurs by Src-targeted and RTK-targeted kinase inhibitors, posing a new drug-resistance mechanism. We reveal that inhibitor-binding to c-Src induces its conformational change to the active form, leading to its association with FAK. Reduction of the inhibitor concentration resulted in the dissociation of inhibitors from the c-Src/FAK complex, which allowed c-Src to phosphorylate FAK and initiated FAK-Grb2-mediated Erk signaling. Unexpectedly, the inhibitors were also able to convert a drug-resistant Src mutant to the active conformation and enhanced cell growth signaling in cells expressing the mutant. We reveal a new molecular basis of drug-resistance that can lead to enhanced cancer cell growth signaling paradoxically evoked by target-based kinase inhibitors, thus providing crucial hints for future development of effective and safe cancer chemotherapy.