Enhanced sensitivity to the HER1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy-resistant tumor cell lines.
OBJECTIVE
Erlotinib (Tarceva, OSI-774) is a potent and specific inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. In phase II clinical studies, oral erlotinib monotherapy has shown antitumor activity in patients with advanced non-small cell lung cancer, head and neck cancer, and ovarian cancer after the failure of standard chemotherapy. We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the HER1/EGFR signaling pathways for survival.


METHODS
The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive, parental, and chemoresistant tumor cell lines.


RESULTS
Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180. The IC(50) values of erlotinib in the resistant cell lines were 2- to 20-fold lower than those in the corresponding parental cell lines. This enhanced sensitivity to erlotinib correlated with higher HER1/EGFR and phospho-HER1/EGFR expression when compared with the corresponding parental cell lines. Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib. AE-ME180/CDDP-resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did.


CONCLUSIONS
Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to HER1/EGFR inhibitors, which correlates with increased HER1/EGFR expression. These data may explain some of the observed clinical activity of HER1/EGFR inhibitors in patients previously treated with multiple therapies. HER1/EGFR tyrosine kinase inhibitors may be more effective as second- or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens.
Dai
Qun
Q
Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 11 East 210th Street, Bronx, NY 10467, USA.
Ling
Yi-He
YH
Lia
Marie
M
Zou
Yi-Yu
YY
Kroog
Glenn
G
Iwata
Kenneth K
KK
Perez-Soler
Roman
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin