ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer.
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC.
Department of Internal Medicine, 3(rd) Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of Korea.
Eun Young
EY
Kim
Department of Internal Medicine, 3(rd) Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of Korea.
Ji Ye
JY
Jung
Department of Internal Medicine, 8(th) Floor Annex Bldg, Gangnam Severance Hospital, Yonsei University College of Medicine, 211-Eonju-ro, Gangnam-gu, 06273, Seoul, Rep of Korea.
Arum
A
Kim
Department of Internal Medicine, 8(th) Floor Annex Bldg, Gangnam Severance Hospital, Yonsei University College of Medicine, 211-Eonju-ro, Gangnam-gu, 06273, Seoul, Rep of Korea. Electronic address: yschang@yuhs.ac.
Yoon Soo
YS
Chang
Department of Internal Medicine, 3(rd) Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of Korea.
Se Kyu
SK
Kim
D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015415:Biomarkers; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C501332:ABT-737; D015415:Biomarkers; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D002945:Cisplatin