Tags

Type your tag names separated by a space and hit enter

Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers.
Clin Cancer Res 2008; 14(21):6963-73CC

Abstract

PURPOSE

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined.

EXPERIMENTAL DESIGN

We examined the relationship of EGFR ligands, EGF, transforming growth factor-alpha,and amphiregulin and the efficacy of gefitinib and cetuximab in EGFR wild-type NSCLC (n=10) and head and neck squamous cell carcinoma (n=4) cell lines. We compared amphiregulin expression using immunohistochemistry in EGFR wild-type NSCLC patients (n=24) that developed either stable or progressive disease following erlotinib or gefitinib treatment.

RESULTS

Cell lines which produced >or=20 pmol/L amphiregulin, as detected by an ELISA, were significantly more likely to be growth inhibited by both gefitinib and cetuximab than those that produced minimal or no amphiregulin. In these cell lines, both cetuximab and gefitinib led to cell cycle arrest at the G(1)-S boundary and was associated with preferential inhibition of extracellular signal-regulated kinase 1/2 but not Akt signaling. Amphiregulin expression was significantly higher in NSCLC patients that developed stable disease compared with those that developed disease progression following gefitinib or erlotinib treatment.

CONCLUSIONS

Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies.

Authors+Show Affiliations

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18980991

Citation

Yonesaka, Kimio, et al. "Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 14, no. 21, 2008, pp. 6963-73.
Yonesaka K, Zejnullahu K, Lindeman N, et al. Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clin Cancer Res. 2008;14(21):6963-73.
Yonesaka, K., Zejnullahu, K., Lindeman, N., Homes, A. J., Jackman, D. M., Zhao, F., ... Jänne, P. A. (2008). Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 14(21), pp. 6963-73. doi:10.1158/1078-0432.CCR-08-0957.
Yonesaka K, et al. Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers. Clin Cancer Res. 2008 Nov 1;14(21):6963-73. PubMed PMID: 18980991.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. AU - Yonesaka,Kimio, AU - Zejnullahu,Kreshnik, AU - Lindeman,Neal, AU - Homes,Alison J, AU - Jackman,David M, AU - Zhao,Feng, AU - Rogers,Andrew M, AU - Johnson,Bruce E, AU - Jänne,Pasi A, PY - 2008/11/5/pubmed PY - 2008/12/20/medline PY - 2008/11/5/entrez SP - 6963 EP - 73 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 14 IS - 21 N2 - PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined. EXPERIMENTAL DESIGN: We examined the relationship of EGFR ligands, EGF, transforming growth factor-alpha,and amphiregulin and the efficacy of gefitinib and cetuximab in EGFR wild-type NSCLC (n=10) and head and neck squamous cell carcinoma (n=4) cell lines. We compared amphiregulin expression using immunohistochemistry in EGFR wild-type NSCLC patients (n=24) that developed either stable or progressive disease following erlotinib or gefitinib treatment. RESULTS: Cell lines which produced >or=20 pmol/L amphiregulin, as detected by an ELISA, were significantly more likely to be growth inhibited by both gefitinib and cetuximab than those that produced minimal or no amphiregulin. In these cell lines, both cetuximab and gefitinib led to cell cycle arrest at the G(1)-S boundary and was associated with preferential inhibition of extracellular signal-regulated kinase 1/2 but not Akt signaling. Amphiregulin expression was significantly higher in NSCLC patients that developed stable disease compared with those that developed disease progression following gefitinib or erlotinib treatment. CONCLUSIONS: Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/18980991/Autocrine_production_of_amphiregulin_predicts_sensitivity_to_both_gefitinib_and_cetuximab_in_EGFR_wild_type_cancers_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18980991 DB - PRIME DP - Unbound Medicine ER -