We have located links that may give you full text access.
Journal Article
Research Support, N.I.H., Extramural
Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC.
Journal of Thoracic Oncology 2013 September
INTRODUCTION: For the majority of patients with non-small-cell lung cancer (NSCLC), response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is suboptimal. In models of acquired resistance to EGFR-TKI, activation of Akt phosphorylation is frequently observed. Because Akt activation results in downstream initiation of cap-dependent protein translation, we hypothesized that a strategy of targeting cap-dependent translation in combination with erlotinib might enhance therapy.
METHODS: NSCLC cells that are wild type for EGFR were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with epidermal growth factor. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum-replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and two different cap-dependent translation inhibitors were done to assess the effect on cell viability.
RESULTS: EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and extracellular regulated kinase, ERK 1/2, resulting in maintenance of eukaryotic initiation factor 4F (eIF4F) activation. eIF4F cap-complex formation is maintained in erlotinib-resistant cells, but not in erlotinib-sensitive cells. Finally, using an antisense oligonucleotide against eukaryotic translation initiation factor 4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib.
CONCLUSION: The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.
METHODS: NSCLC cells that are wild type for EGFR were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with epidermal growth factor. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum-replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and two different cap-dependent translation inhibitors were done to assess the effect on cell viability.
RESULTS: EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and extracellular regulated kinase, ERK 1/2, resulting in maintenance of eukaryotic initiation factor 4F (eIF4F) activation. eIF4F cap-complex formation is maintained in erlotinib-resistant cells, but not in erlotinib-sensitive cells. Finally, using an antisense oligonucleotide against eukaryotic translation initiation factor 4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib.
CONCLUSION: The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.
Full text links
Related Resources
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app