BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer.
BACKGROUND
Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes.


METHODS
Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed.


RESULTS
BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values ≥3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352-5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002).


CONCLUSIONS
BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Tomohiro
T
Kubo
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Yutaka
Y
Kawano
Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan.
Nobuaki
N
Himuro
Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan.
Shintaro
S
Sugita
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Yasushi
Y
Sato
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Kazuma
K
Ishikawa
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Kohichi
K
Takada
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Kazuyuki
K
Murase
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Koji
K
Miyanishi
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Tsutomu
T
Sato
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Rishu
R
Takimoto
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Masayoshi
M
Kobune
Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, 060-8543, Japan.
Takayuki
T
Nobuoka
Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, 060-8543, Japan.
Koichi
K
Hirata
Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima, Tokushima, 770-8503, Japan.
Tetsuji
T
Takayama
Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan.
Mitsuru
M
Mori
Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan.
Tadashi
T
Hasegawa
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan. jkato@sapmed.ac.jp.
Junji
J
Kato
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D065228:Non-Randomized Controlled Trials as Topic; D010094:Oxonic Acid / Q000008:administration & dosage; D010446:Peptide Fragments / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D005641:Tegafur / Q000008:administration & dosage; D055815:Young Adult; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
C494772:BAK1 protein, human; C474007:Bax protein (53-86); D014408:Biomarkers, Tumor; D004338:Drug Combinations; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D050998:bcl-2 Homologous Antagonist-Killer Protein; C079198:S 1 (combination); D005641:Tegafur; D000077143:Docetaxel; D010094:Oxonic Acid; D002945:Cisplatin
BAK; BH3; Docetaxel; Gastric cancer