AZD9291 overcomes T790 M-mediated resistance through degradation of EGFR L858R/T790M in non-small cell lung cancer cells

Summary

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 EGFR^L858R/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 EGFR^L858R/T790M to AZD9291. In H1975 cells harboring EGFR^L858R/T790M, AZD9291 potently inhibited cellular growth and EGFR signaling pathways together with depletion of mutant EGFR protein. AZD9291-induced depletion of EGFR^L858R/T790M protein was abrogated through inhibition of the proteasome with MG132. However, AZD9291 had no effect on protein levels of EGFR^WT and EGFR^L858R. 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 EGFR^L858R/T790M protein levels in xenograft tumors. Taken together, our results provide a potential mechanism for the sensitivity of EGFR^L858R/T790M cells to AZD9291 and suggest that AZD9291 may be effective in cases of T790 M-positive EGFR resistance.

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