Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy.
The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma (SCC) of the head and neck. Most patients, however, do not respond or develop resistance to this agent. Mammalian target of rapamycin (mTOR) is involved in the pathogenesis of SCC of the head and neck (SCCHN). This study aimed to determine if targeting mTOR in combination with EGFR is effective in SCC, and to develop early pharmacodynamic markers of efficacy. Two SCC cell lines, one resistant (HEP2) and one of intermediate susceptibility (Detroit 562) to EGFR inhibitors, were xenografted in vivo and treated with an mTOR inhibitor (temsirolimus), an EGFR inhibitor (erlotinib) or a combination of both. Temsirolimus exerted superior growth arrest in both cell lines than erlotinib. The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line. Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration (FNA) biopsies early after treatment using phospho MAPK, Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination, the only group where regressions were seen. In conclusion, an mTOR inhibitor showed antitumor activity in EGFR-resistant SCC cell lines. Marked antitumor effects were associated with dual pathway inhibition, which were detected by early FNA biopsies.
Jimeno
A
A
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 1M89, Baltimore, MD 21231-1000, USA.
Kulesza
P
P
Wheelhouse
J
J
Chan
A
A
Zhang
X
X
Kincaid
E
E
Chen
R
R
Clark
D P
DP
Forastiere
A
A
Hidalgo
M
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006131:Growth Inhibitors / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C401859:temsirolimus; D000069347:Erlotinib Hydrochloride; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus