AZD9291 overcomes T790 M-mediated resistance through degradation of EGFRL858R/T790M in non-small cell lung cancer cells

The discovery of activating mutations of epidermal growth factor receptor (EGFR) has resulted in the development of more effective treatments for non-small cell lung cancer (NSCLC). Although first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit, acquired resistance often occurs, most commonly (>50 %) via a T790 M resistance mutation. Although AZD9291 is selective for both T790 M and activating EGFR mutations over wild-type EGFR, it is highly active when T790 M is present, especially EGFRL858R/T790M, and modestly active when T790 M is absent. The aim of this study was to elucidate the underlying mechanism of the high sensitivity of NSCLC cells harboring EGFRL858R/T790M to AZD9291. In H1975 cells harboring EGFRL858R/T790M, AZD9291 potently inhibited cellular growth and EGFR signaling pathways together with depletion of mutant EGFR protein. AZD9291-induced depletion of EGFRL858R/T790M protein was abrogated through inhibition of the proteasome with MG132. However, AZD9291 had no effect on protein levels of EGFRWT and EGFRL858R. In addition, AZD9291 induced apoptosis and caused expression changes in cell cycle-related genes. Moreover, oral administration of AZD9291 as a single agent induced tumor regression in vivo in a H1975 tumor xenograft model and reduced EGFRL858R/T790M protein levels in xenograft tumors. Taken together, our results provide a potential mechanism for the sensitivity of EGFRL858R/T790M cells to AZD9291 and suggest that AZD9291 may be effective in cases of T790 M-positive EGFR resistance.