Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression.
Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We therefore investigated the mechanisms mediating resistance to the therapeutic activities of SCH66336 in HNSCC and NSCLC. Our various analyses showed that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of SCH66336 in HNSCC and NSCLC cells. Treatment with SCH66336 activated the IGF-IR/phosphatidylinositol 3-kinase/Akt pathway, leading to increased mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin in a subset of HNSCC and NSCLC cell lines that were insensitive to the apoptotic activities of the drug. Inhibition of IGF-IR, Akt, or mTOR or the knockdown of survivin expression abolished resistance to SCH66336 and induced apoptosis in the cells. Overexpression of survivin by the use of adenoviral vector protected SCH66336-sensitive HNSCC cells from the apoptotic activities of the drug. Our results suggest that expression of phosphorylated IGF-IR, phosphorylated Akt, phosphorylated mTOR, and survivin serves as biological markers of SCH66336 responsiveness in HNSCC and NSCLC cells and that SCH66336 induces survivin expression through an IGF-IR/Akt/mTOR-dependent pathway. Thus, combining inhibitors of IGF-IR, phosphatidylinositol 3-kinase/Akt, mTOR, or survivin with SCH66336 may be an effective anticancer therapeutic strategy for patients with HNSCC or NSCLC.
Oh
Seung Hyun
SH
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jin
Quanri
Q
Kim
Edward S
ES
Khuri
Fadlo R
FR
Lee
Ho-Young
HY
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases; C107489:BIRC5 protein, human; C546842:MTOR protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes