title: WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors.
abstract: Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA.
authors.affiliation: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Asahi-ku, Yokohama, Japan. ysakuma@gancen.asahi.yokohama.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Shoichi
authors.initials: S
authors.lastname: Matsukuma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Nakayama
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yokose
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kameda
authors.forename: Shiro
authors.initials: S
authors.lastname: Koizume
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D023102:Anoikis / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D052117:Benzodioxoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C012589:trichostatin A; C571455:WZ4002; C515233:saracatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; C528561:navitoclax