JOURNAL ARTICLE

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

Bo Mi Ku, Yeon-Hee Bae, Jiae Koh, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Investigational New Drugs 2016, 34 (4): 407-15
27044261
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read
27044261
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"