High TUBB3 expression, an independent prognostic marker in patients with early non-small cell lung cancer treated by preoperative chemotherapy, is regulated by K-Ras signaling pathway
©2012 AACR.
We assessed the prognostic and predictive value of β-tubulin III (TUBB3) expression, as determined by immunohistochemistry, in 412 non-small cell lung cancer (NSCLC) specimens from early-stage patients who received neoadjuvant chemotherapy (paclitaxel- or gemcitabine-based) in a phase III trial (IFCT-0002). We also correlated TUBB3 expression with K-Ras and EGF receptor (EGFR) mutations in a subset of 208 cryopreserved specimens. High TUBB3 protein expression was associated with nonsquamous cell carcinomas (P < 0.001) and K-Ras mutation (P < 0.001). The 127 (30.8%) TUBB3-negative patients derived more than 1 year of overall survival advantage, with more than 84 months median overall survival versus 71.7 months for TUBB3-positive patients [HR, 1.58; 95% confidence interval (CI), 1.11-2.25)]. This prognostic value was confirmed in multivariate analysis (adjusted HR for death, 1.51; 95% CI, 1.04-2.21; P = 0.031) with a bootstrapping validation procedure. TUBB3 expression was associated with nonresponse to chemotherapy (adjusted HR, 1.31; 95% CI, 1.01-1.70; P = 0.044) but had no predictive value (taxane vs. gemcitabine). Taking account of these clinical findings, we further investigated TUBB3 expression in isogenic human bronchial cell lines only differing by K-Ras gene status and assessed the effect of K-Ras short interfering RNA (siRNA) mediated depletion, cell hypoxia, or pharmacologic inhibitors of K-Ras downstream effectors, on TUBB3 protein cell content. siRNA K-Ras knockdown, inhibition of RAF/MEK (MAP-ERK kinase) and phosphoinositide 3-kinase (PI3K)/AKT signaling, and hypoxia were shown to downregulate TUBB3 expression in bronchial cells. This study is the first one to identify K-Ras mutations as determinant of TUBB3 expression, a chemoresistance marker. Our in vitro data deserve studies combining standard chemotherapy with anti-MEK or anti-PI3K drugs in patients with TUBB3-overexpressing tumors.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2012 |
|---|---|
| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
Molecular cancer therapeutics - 11(2012), 5 vom: 03. Mai, Seite 1203-13 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Levallet, Guénaëlle [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Biomarkers, Tumor |
|---|
| Anmerkungen: |
Date Completed 18.02.2013 Date Revised 30.09.2020 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1535-7163.MCT-11-0899 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM216144973 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM216144973 | ||
| 003 | DE-627 | ||
| 005 | 20231224031102.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2012 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1535-7163.MCT-11-0899 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0720.xml |
| 035 | |a (DE-627)NLM216144973 | ||
| 035 | |a (NLM)22411898 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Levallet, Guénaëlle |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a High TUBB3 expression, an independent prognostic marker in patients with early non-small cell lung cancer treated by preoperative chemotherapy, is regulated by K-Ras signaling pathway |
| 264 | 1 | |c 2012 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.02.2013 | ||
| 500 | |a Date Revised 30.09.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2012 AACR | ||
| 520 | |a We assessed the prognostic and predictive value of β-tubulin III (TUBB3) expression, as determined by immunohistochemistry, in 412 non-small cell lung cancer (NSCLC) specimens from early-stage patients who received neoadjuvant chemotherapy (paclitaxel- or gemcitabine-based) in a phase III trial (IFCT-0002). We also correlated TUBB3 expression with K-Ras and EGF receptor (EGFR) mutations in a subset of 208 cryopreserved specimens. High TUBB3 protein expression was associated with nonsquamous cell carcinomas (P < 0.001) and K-Ras mutation (P < 0.001). The 127 (30.8%) TUBB3-negative patients derived more than 1 year of overall survival advantage, with more than 84 months median overall survival versus 71.7 months for TUBB3-positive patients [HR, 1.58; 95% confidence interval (CI), 1.11-2.25)]. This prognostic value was confirmed in multivariate analysis (adjusted HR for death, 1.51; 95% CI, 1.04-2.21; P = 0.031) with a bootstrapping validation procedure. TUBB3 expression was associated with nonresponse to chemotherapy (adjusted HR, 1.31; 95% CI, 1.01-1.70; P = 0.044) but had no predictive value (taxane vs. gemcitabine). Taking account of these clinical findings, we further investigated TUBB3 expression in isogenic human bronchial cell lines only differing by K-Ras gene status and assessed the effect of K-Ras short interfering RNA (siRNA) mediated depletion, cell hypoxia, or pharmacologic inhibitors of K-Ras downstream effectors, on TUBB3 protein cell content. siRNA K-Ras knockdown, inhibition of RAF/MEK (MAP-ERK kinase) and phosphoinositide 3-kinase (PI3K)/AKT signaling, and hypoxia were shown to downregulate TUBB3 expression in bronchial cells. This study is the first one to identify K-Ras mutations as determinant of TUBB3 expression, a chemoresistance marker. Our in vitro data deserve studies combining standard chemotherapy with anti-MEK or anti-PI3K drugs in patients with TUBB3-overexpressing tumors | ||
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a TUBB3 protein, human |2 NLM | |
| 650 | 7 | |a Tubulin |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 700 | 1 | |a Bergot, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Antoine, Martine |e verfasserin |4 aut | |
| 700 | 1 | |a Creveuil, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Adriana O |e verfasserin |4 aut | |
| 700 | 1 | |a Beau-Faller, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a de Fraipont, Florence |e verfasserin |4 aut | |
| 700 | 1 | |a Brambilla, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Levallet, Jérôme |e verfasserin |4 aut | |
| 700 | 1 | |a Morin, Franck |e verfasserin |4 aut | |
| 700 | 1 | |a Westeel, Virginie |e verfasserin |4 aut | |
| 700 | 1 | |a Wislez, Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Quoix, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Debieuvre, Didier |e verfasserin |4 aut | |
| 700 | 1 | |a Dubois, Fatéméh |e verfasserin |4 aut | |
| 700 | 1 | |a Rouquette, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Pujol, Jean-Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Moro-Sibilot, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Camonis, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Zalcman, Gérard |e verfasserin |4 aut | |
| 700 | 0 | |a Intergroupe Francophone de Cancérologie Thoracique (IFCT) |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular cancer therapeutics |d 2001 |g 11(2012), 5 vom: 03. Mai, Seite 1203-13 |w (DE-627)NLM122520580 |x 1538-8514 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2012 |g number:5 |g day:03 |g month:05 |g pages:1203-13 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1535-7163.MCT-11-0899 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2012 |e 5 |b 03 |c 05 |h 1203-13 | ||