title: AZD9291 overcomes T790 M-mediated resistance through degradation of EGFR(L858R/T790M) in non-small cell lung cancer cells.
abstract: 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.
authors.affiliation: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Bo Mi
authors.initials: BM
authors.lastname: Ku
authors.affiliation: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Jiae
authors.initials: J
authors.lastname: Koh
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 135-710, South Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 135-710, South Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 135-710, South Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 135-710, South Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea. silk.ahn@samsung.com.|Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 135-710, South Korea. silk.ahn@samsung.com.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
mesh_terms: D000178:Acrylamides / Q000494:pharmacology* / Q000627:therapeutic use; D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human
keywords: AZD9291; Apoptosis; Mutant EGFR; Non-small cell lung cancer; T790 M mutation