CCI-779 (Temsirolimus) Exhibits Increased Anti-tumor Activity in Low EGFR Expressing HNSCC Cell Lines and is Effective in Cells with Acquired Resistance to Cisplatin or Cetuximab

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2015 Apr 19

PMID 25890004

Citations 5

Authors

Franziska Niehr

Wilko Weichert

Albrecht Stenzinger

Volker Budach

Ingeborg Tinhofer

Affiliations

Soon will be listed here.

Abstract

Background: The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells.

Methods: A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated.

Results: We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade.

Conclusions: Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies.

Citing Articles

Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials.

Goel B, Tiwari A, Pandey R, Singh A, Kumar S, Sinha A Transl Oncol. 2022; 21:101426.

PMID: 35460943 PMC: 9046875. DOI: 10.1016/j.tranon.2022.101426.

Shooting at Moving and Hidden Targets-Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas.

Kalafut J, Czerwonka A, Anameric A, Przybyszewska-Podstawka A, Misiorek J, Rivero-Muller A Cancers (Basel). 2021; 13(24).

PMID: 34944837 PMC: 8699303. DOI: 10.3390/cancers13246219.

Current Insights and Advancements in Head and Neck Cancer: Emerging Biomarkers and Therapeutics with Cues from Single Cell and 3D Model Omics Profiling.

Jawa Y, Yadav P, Gupta S, Mathan S, Pandey J, Saxena A Front Oncol. 2021; 11:676948.

PMID: 34490084 PMC: 8418074. DOI: 10.3389/fonc.2021.676948.

Predictive Value of EGFR-PI3K-AKT-mTOR-Pathway Inhibitor Biomarkers for Head and Neck Squamous Cell Carcinoma: A Systematic Review.

de Kort W, Spelier S, Devriese L, van Es R, Willems S Mol Diagn Ther. 2021; 25(2):123-136.

PMID: 33686517 PMC: 7956931. DOI: 10.1007/s40291-021-00518-6.

Application of molecular targeted therapies in the treatment of head and neck squamous cell carcinoma.

Kozakiewicz P, Grzybowska-Szatkowska L Oncol Lett. 2018; 15(5):7497-7505.

PMID: 29725456 PMC: 5920345. DOI: 10.3892/ol.2018.8300.

References

Coppock J, Wieking B, Molinolo A, Gutkind J, Miskimins W, Lee J . Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition. Neoplasia. 2013; 15(6):620-30. PMC: 3664994. DOI: 10.1593/neo.13432. View

Hoffmann T, Sonkoly E, Hauser U, van Lierop A, Whiteside T, Klussmann J . Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma. Oral Oncol. 2008; 44(12):1100-9. DOI: 10.1016/j.oraloncology.2008.02.006. View

Lui V, Hedberg M, Li H, Vangara B, Pendleton K, Zeng Y . Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013; 3(7):761-9. PMC: 3710532. DOI: 10.1158/2159-8290.CD-13-0103. View

Herzog A, Bian Y, Vander Broek R, Hall B, Coupar J, Cheng H . PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer. Clin Cancer Res. 2013; 19(14):3808-19. PMC: 3715575. DOI: 10.1158/1078-0432.CCR-12-2716. View

Ekshyyan O, Rong Y, Rong X, Pattani K, Abreo F, Caldito G . Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther. 2009; 8(8):2255-65. PMC: 2758817. DOI: 10.1158/1535-7163.MCT-08-1184. View

Lu T, Jackson M, Wang B, Yang M, Chance M, Miyagi M . Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010; 107(1):46-51. PMC: 2806709. DOI: 10.1073/pnas.0912493107. View

Bonner J, Harari P, Giralt J, Cohen R, Jones C, Sur R . Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2009; 11(1):21-8. DOI: 10.1016/S1470-2045(09)70311-0. View

Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T . Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010; 120(8):2858-66. PMC: 2912177. DOI: 10.1172/JCI37539. View

Forbes S, Bindal N, Bamford S, Cole C, Kok C, Beare D . COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2010; 39(Database issue):D945-50. PMC: 3013785. DOI: 10.1093/nar/gkq929. View

10.

Schedel F, Pries R, Thode B, Wollmann B, Wulff S, Jocham D . mTOR inhibitors show promising in vitro activity in bladder cancer and head and neck squamous cell carcinoma. Oncol Rep. 2011; 25(3):763-8. DOI: 10.3892/or.2011.1146. View

11.

Satheesha S, Cookson V, Coleman L, Ingram N, Madhok B, Hanby A . Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer. Mol Cancer. 2011; 10:19. PMC: 3055230. DOI: 10.1186/1476-4598-10-19. View

12.

Vilar E, Perez-Garcia J, Tabernero J . Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther. 2011; 10(3):395-403. PMC: 3413411. DOI: 10.1158/1535-7163.MCT-10-0905. View

13.

Gadhikar M, Sciuto M, Alves M, Pickering C, Osman A, Neskey D . Chk1/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53. Mol Cancer Ther. 2013; 12(9):1860-73. PMC: 3955083. DOI: 10.1158/1535-7163.MCT-13-0157. View

14.

Fury M, Lee N, Sherman E, Ho A, Rao S, Heguy A . A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2013; 87(3):479-86. DOI: 10.1016/j.ijrobp.2013.06.2043. View

15.

Endris V, Penzel R, Warth A, Muckenhuber A, Schirmacher P, Stenzinger A . Molecular diagnostic profiling of lung cancer specimens with a semiconductor-based massive parallel sequencing approach: feasibility, costs, and performance compared with conventional sequencing. J Mol Diagn. 2013; 15(6):765-75. DOI: 10.1016/j.jmoldx.2013.06.002. View

16.

Li Q, Song X, Ji Y, Jiang H, Xu L . The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro. Biochem Biophys Res Commun. 2013; 440(4):701-6. DOI: 10.1016/j.bbrc.2013.09.130. View

17.

Molinolo A, Marsh C, El Dinali M, Gangane N, Jennison K, Hewitt S . mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res. 2012; 18(9):2558-68. PMC: 3443560. DOI: 10.1158/1078-0432.CCR-11-2824. View

18.

Oiso S, Ikeda R, Nakamura K, Takeda Y, Akiyama S, Kariyazono H . Involvement of NF-κB activation in the cisplatin resistance of human epidermoid carcinoma KCP-4 cells. Oncol Rep. 2012; 28(1):27-32. DOI: 10.3892/or.2012.1801. View

19.

Sun Z, Zhang L, Hall B, Bian Y, Gutkind J, Kulkarni A . Chemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model. Clin Cancer Res. 2012; 18(19):5304-13. PMC: 3463723. DOI: 10.1158/1078-0432.CCR-12-1371. View

20.

Cassell A, Freilino M, Lee J, Barr S, Wang L, Panahandeh M . Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models. Neoplasia. 2012; 14(11):1005-14. PMC: 3514742. DOI: 10.1593/neo.121212. View