Open AccessGM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non‐small cell lung cancer
Author(s) -
Noguchi Mariko,
Suzuki Tomoko,
Kabayama Kazuya,
Takahashi Hiroki,
Chiba Hirofumi,
Shiratori Masanori,
Abe Shosaku,
Watanabe Atsushi,
Satoh Masaaki,
Hasegawa Tadashi,
Tagami Seiichi,
Ishii Atsushi,
Saitoh Masaki,
Kaneko Masanori,
Iseki Ken,
Igarashi Yasuyuki,
Inokuchi Jinichi
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00578.x
Subject(s) - gefitinib , epidermal growth factor receptor , adenocarcinoma , lung cancer , cancer research , biology , erlotinib , tyrosine kinase inhibitor , epidermal growth factor , tyrosine kinase , cancer , cell growth , cell culture , receptor , pathology , medicine , biochemistry , genetics
Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT‐I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT‐I mRNA as well as GM3 in 40 tumor tissues surgically removed from non‐small cell lung cancer patients. Adenocarcinoma tissues expressed SAT‐I mRNA levels that were significantly higher than those of squamous and other carcinomas ( P < 0.0001). Moreover, the SAT‐I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas ( P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT‐I mRNA and epidermal growth factor receptor (EGFR)‐tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR‐TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC 50 values for gefitinib and AG1478 decreased dramatically with increasing SAT‐I mRNA levels ( R 2 = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR‐TK inhibitors, the SAT‐I gene was introduced stably into a GM3‐negative clone of murine 3LL lung cancer cells to produce GM3‐reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3‐reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT‐I mRNA in lung biopsy samples from non‐small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR‐TK inhibitors. ( Cancer Sci 2007; 98: 1625–1632)