The Combination of Trametinib, a MEK Inhibitor, and Temsirolimus, an mTOR Inhibitor, Radiosensitizes Lung Cancer Cells

被引：4

作者：

Kim, Seo Yun ^{[1
]}

Jeong, Eun-Hui ^{[1
]}

Lee, Tae-Gul ^{[1
,2
]}

Kim, Hye-Ryoun ^{[1
]}

Kim, Cheol Hyeon ^{[1
]}

机构：

[1] Korea Canc Ctr Hosp, Dept Internal Med, Div Pulmonol, Seoul, South Korea

[2] Korea Univ, Sch Life Sci & Biotechnol, Dept Biotechnol, Seoul, South Korea

来源：

ANTICANCER RESEARCH | 2021年 / 41卷 / 06期

关键词：

Lung cancer; MEK inhibitor; mTOR inhibitor; radiation; trametinib; temsirolimus; RADIOTHERAPY; RADIATION; RESISTANCE; SURVIVAL; PATHWAY; MULTICENTER; DABRAFENIB; KINASE; TARGET;

D O I：

10.21873/anticanres.15070

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background/Aim: We evaluated the radiosensitizing effect of the combination treatment of trametinib, a MEK inhibitor, and temsirolimus, an mTOR inhibitor, on non-small cell lung carcinoma (NSCLC) cells. Materials and Methods: The effects of combining trametinib and temsirolimus with radiation in NSCLC cell lines were evaluated using clonogenic survival and apoptosis assays. DNA double-strand breaks and cell cycle distribution were analyzed using flow cytometry. Tumor volume was measured to determine the radiosensitivity in lung cancer xenograft models. Results: Exposure of lung cancer cells to a combination of trametinib and temsirolimus reduced clonogenic survival and promoted radiation-induced apoptosis. Combined inhibition of MEK and mTOR induced prolonged expression of gamma H2AX after irradiation and resulted in prolonged G(2)/M cell cycle arrest after irradiation in A549 cells. In vivo studies revealed that co-administration of the drugs sensitizes lung cancer xenografts to radiotherapy. Conclusion: The combination of trametinib and temsirolimus can enhance lung cancer radiosensitivity in vitro and in vivo.

引用

页码：2885 / 2894

页数：10

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[21] A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors [J].

Grilley-Olson, J. E. ;

Bedard, P. L. ;

Fasolo, A. ;

Cornfeld, M. ;

Cartee, L. ;

Razak, A. R. Abdul ;

Stayner, L. -A. ;

Wu, Y. ;

Greenwood, R. ;

Singh, R. ;

Lee, C. B. ;

Bendell, J. ;

Burris, H. A. ;

Del Conte, G. ;

Sessa, C. ;

Infante, J. R. .

INVESTIGATIONAL NEW DRUGS, 2016, 34 (06) :740-749

[22] A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors [J].

J. E. Grilley-Olson ;

P. L. Bedard ;

A. Fasolo ;

M. Cornfeld ;

L. Cartee ;

A. R. Abdul Razak ;

L.-A. Stayner ;

Y. Wu ;

R. Greenwood ;

R. Singh ;

C. B. Lee ;

J. Bendell ;

H. A. Burris ;

G. Del Conte ;

C. Sessa ;

J. R. Infante .

Investigational New Drugs, 2016, 34 :740-749

[23] mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells [J].

Stepanenko, A. A. ;

Andreieva, S. V. ;

Korets, K. V. ;

Mykytenko, D. O. ;

Baklaushev, V. P. ;

Chekhonin, V. P. ;

Dmitrenko, V. V. .

GENE, 2016, 579 (01) :58-68

[24] Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors [J].

Monica Mita ;

Siqing Fu ;

Sarina Anne Piha-Paul ;

Filip Janku ;

Alain Mita ;

Ronald Natale ;

Wei Guo ;

Charles Zhao ;

Razelle Kurzrock ;

Aung Naing .

Investigational New Drugs, 2017, 35 :616-626

[25] Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: In vitro and in vivo [J].

Liu, Wenlei ;

Huang, Shengyun ;

Chen, Zhanwei ;

Wang, Huachun ;

Wu, Haiwei ;

Zhang, Dongsheng .

PATHOLOGY RESEARCH AND PRACTICE, 2014, 210 (11) :764-769

[26] ONC201 and an MEK Inhibitor Trametinib Synergistically Inhibit the Growth of Triple-Negative Breast Cancer Cells [J].

Lim, Bora ;

Peterson, Christine B. ;

Davis, Alexander ;

Cho, Elin ;

Pearson, Troy ;

Liu, Huey ;

Hwang, Minha ;

Ueno, Naoto Tada ;

Lee, Jangsoon .

BIOMEDICINES, 2021, 9 (10)

[27] Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study [J].

Ragon, Brittany Knick ;

Odenike, Olatoyosi ;

Baer, Maria R. ;

Stock, Wendy ;

Borthakur, Gautam ;

Patel, Keyur ;

Han, Lina ;

Chen, Helen ;

Ma, Helen ;

Joseph, Loren ;

Zhao, Yang ;

Baggerly, Keith ;

Konopleva, Marina ;

Jain, Nitin .

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2019, 19 (07) :431-+

[28] A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors [J].

Tolcher, A. W. ;

Bendell, J. C. ;

Papadopoulos, K. P. ;

Burris, H. A., III ;

Patnaik, A. ;

Jones, S. F. ;

Rasco, D. ;

Cox, D. S. ;

Durante, M. ;

Bellew, K. M. ;

Park, J. ;

Le, N. T. ;

Infante, J. R. .

ANNALS OF ONCOLOGY, 2015, 26 (01) :58-64

[29] A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies [J].

Trivedi, Neel D. ;

Armstrong, Samantha ;

Wang, Hongkun ;

Hartley, Marion ;

Deeken, John ;

He, A. Ruth ;

Subramaniam, Deepa ;

Melville, Heather ;

Albanese, Chris ;

Marshall, John L. ;

Hwang, Jimmy ;

Pishvaian, Michael J. .

CANCER MEDICINE, 2021, 10 (06) :1944-1954

[30] Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus [J].

Liu, Xiaochun ;

Kambrick, Susan ;

Fu, Siqing ;

Naing, Aung ;

Subbiah, Vivek ;

Blumenschein, George R. ;

Glisson, Bonnie S. ;

Kies, Merrill S. ;

Tsimberidou, Apostolia M. ;

Wheler, Jennifer J. ;

Zinner, Ralph G. ;

Hong, David S. ;

Kurzrock, Razelle ;

Piha-Paul, Sarina A. .

ONCOTARGET, 2016, 7 (17) :23227-23238

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