Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non–small-cell lung, pancreatic, colon, and breast tumors

• Published in: Molecular cancer therapeutics Vol. 5; no. 11; pp. 2676 - 2684
• Main Authors: Buck, Elizabeth, Eyzaguirre, Alexandra, Brown, Eric, Petti, Filippo, McCormack, Siobhan, Haley, John D, Iwata, Kenneth K, Gibson, Neil W, Griffin, Graeme
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-11-2006
• Subjects: Akt; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; combination; Dose-Response Relationship, Drug; Drug Synergism; EGFR; erlotinib; Erlotinib Hydrochloride; Female; HCT116 Cells; HT29 Cells; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mice; Mice, Transgenic; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Quinazolines - pharmacology; Quinazolines - therapeutic use; rapamycin; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Sirolimus - pharmacology; Sirolimus - therapeutic use
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0166

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated
by EGFR is the phosphatidylinositol 3′-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads
to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin
(mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the
sensitivity of non–small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is
dependent on inhibition of the phosphatidylinositol 3′-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There
can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting
EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention.
Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived
from a variety of tissue types (non–small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular
signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in
all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate
rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the
combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended
in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance
response to erlotinib. [Mol Cancer Ther 2006;5(11):2676–84]