Previous studies have demonstrated that wild-type (WT) EGFRs are activated by an allosteric mechanism in which a ‘donor’ tyrosine kinase domain (TKD) monomer contacts an ‘acceptor’ TKD monomer, leading to its activation. Here, we present biochemical reconstitution data demonstrating that receptor activation by the most frequently occurring EGFR mutations found in lung cancer does not adhere to this mechanism. Mutated EGFRs hyperphosphorylate their WT counterparts and appear to adopt a conformation that allows them to function as acceptors but not as donors to WT EGFR. As acceptors, the mutated EGFRs also show enhanced association with WT EGFR. We suggest the term “superacceptor activity” to describe this directionally-limited mutant-specific mechanism of EGFR transactivation. Mutated EGFRs also hyperphosphorylate the related ErbB family member, ErbB-2, in a similar manner. Collectively, these data provide insights into a mechanism for activation of lung cancer-associated mutant EGFRs. Since WT EGFRs are usually present in EGFR mutant tumor cells, our studies additionally argue that WT EGFRs contribute to tumorigenesis and may alter sensitivity to EGFR-targeted therapy.

Citation Format: Monica L. Red Brewer, Darson Lai, Mark A. Lemmon, William Pao. Mechanism for activation of mutated EGF receptors in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2013-1106