Transglutaminase 2 Expression Predicts Progression Free Survival in Non-Small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Abstract

Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and in the constitutive activation of nuclear factor kappa B (NF-κB). We investigated the association of non-small cell lung cancer (NSCLC) treatment efficacy with TG2 and NF-κB expression in 120 patients: 102 with adenocarcinoma and 18 with other histologic types. All patients underwent surgery; 88 received adjuvant chemotherapy, with 28 receiving platinum-based doublet chemotherapy as first-line treatment and 29 receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients' TG2 and NF-κB expression values were calculated semiquantitatively. The median TG2 value was 50 (range, 0-300) and the median NF-κB value was 20 (range, 0-240). Disease-free survival did not differ between the low- and high-TG2 groups. Among patients who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was longer in the low-TG2 group than in the high-TG2 group (11.0 vs. 7.0 months; P=0.330). Among those who received EGFR-TKI therapy, PFS was also longer in the low-TG2 group than in the high-TG 2 group (11.0 vs. 2.0 months; P=0.013). Similarly, in EGFR wild-type patients treated with EGFR-TKI, PFS was longer in patients with low TG2 expression (9.0 vs. 2.0 months; P=0.013). TG2 expression levels can predict PFS in patients with NSCLC treated with EGFR-TKI.

Prognostic value of transglutaminase 2 in non-small cell lung cancer patients

“…These evidences thus suggest that TG2 may play important roles in cancer cell survival and cancer metastasis or recurrence during clinical treatment. Of note, Jeong JH et al has recently reported that TG2 expression correlated to the DFS and progression-free survival (PFS) for NSCLC in a small cohort containing enrolling 29 patients [ 30 ]. In another study with a larger cohort containing 429 NSCLC cases, Choi CM., et al has also reported significant correlation between strong TG 2 expression and shorter DFS in the non-adenocarcinoma subtype of NSCLC, but they did not identify similar correlation in the adenocarcinoma subtype [ 31 ].…”

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

“…Two independent studies of non‐small cell lung cancer patients show that elevated TG2 level predicts disease recurrence and shorter disease free survival, and suggest that TG2 level may be a prognostic marker of disease progression . Moreover, in chemotherapy patients, progression free survival is lengthened if the patients have low tumor levels of TG2 . Other studies also support a role for TG2 in this disease.…”

Transglutaminase is a tumor cell and cancer stem cell survival factor

“…Glioma TG2 increases EGFR level [87] and cAMP signaling [86] TG2 confers resistance to doxorubicin [85], TG2 confers resistance to N,N 0 -bis(2-chloroethyl)-N-nitrosourea treatment [82,83] TG2 elevated in glioma cancer stem cells and required for survival [140] Epidermal squamous cell carcinoma TG2 does not alter NFkB signaling [89,154] TG2 enhances EMT [88,89,154] TG2 enhances tumor formation [88,89,154] TG2 overexpressed in epidermal squamous cell carcinoma cancer stem cells and required for survival [88][89][90] Melanoma TG2 interacts with a9b1 and a5b1 integrins leading to enhanced adhesion [97], TG2 interacts with b1 and b5 integrin to enhance attachment [95], TG2 is internalized by GPR56 leading to reduced adhesion and matrix crosslinking [110] NFkB signaling increases Rac1 and FAK signaling and TG2 level [98] TG2 crosslinking activity is required for tumor formation [110] Lung TG2 confers drug resistance [111,113] TG2 includes EMT marker expression [112] Colon TG2 does not alter NFkB signaling [96] TG2 does not alter sensitivity to doxorubicin [96] TG2 increases and interacts with b3-integrin to reduce migration [96] that converts it from a folded/closed (signaling) conformation to an open/extended (non-signaling) configuration. Treatment of cancer stem cells with this agent shows that it efficiently reduces cancer stem cell survival, migration, and invasion [88][89][90].…”