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01-03-2020 | NSCLC | Original Article

Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients

Authors: M. Teresa Agulló-Ortuño, Inmaculada García-Ruiz, C. Vanesa Díaz-García, Ana B. Enguita, Virginia Pardo-Marqués, Elena Prieto-García, Santiago Ponce, Lara Iglesias, Jon Zugazagoitia, José A. López-Martín, Luis Paz-Ares, Juan A. Nuñez

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2020

Abstract

Purpose

Therapeutic options for cancer patients have increased in the last years, although drugs resistance problem remains unresolved. Genetic background in individual susceptibility to cancer treatment could influence the therapy responses. The aim of this study was to explore the feasibility of using blood 4 genes (AEG-1, BRCA-1, REV3L and TYMS) expression levels as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer.

Methods

Sixteen patients from the Medical Oncology Department at “12 de Octubre” Hospital, were included in the study. Total mRNA was isolated from blood samples, and gene expression was analyzed by RT-qPCR. A panel of lung tumor cell lines were used in cell proliferation tests and siRNA-mediated silencing assays.

Results

Similarity between blood gene expression levels and protein expression in matched tumor tissue was observed in 54.54% (REV3L) and 81.81% (TYMS) of cases. Gene expression of REV3L and TYMS in blood correlated directly and inversely, respectively, with progression-free survival and overall survival in the patients from our cohort. In tumor cell lines, the knockdown of REV3L conferred resistance to pemetrexed treatment, and the TYMS silencing increased the pemetrexed sensitivity of tumor cells.

Conclusions

The use of peripheral blood samples for expression quantification of interest genes is an affordable method with promising results in the evaluation of response to pemetrexed treatment. Therefore, expression levels of REV3L and TYMS genes might be used as predictive biomarkers in advanced NSCLC patients.

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Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin. https://doi.org/10.3322/caac.21332 CrossRefPubMedPubMedCentral

Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG et al (2016) Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. https://doi.org/10.1093/annonc/mdw326 CrossRefPubMed

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. https://doi.org/10.1016/S1470-2045(11)70393-X CrossRefPubMed

Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. https://doi.org/10.1200/JCO.2012.44.2806 CrossRefPubMed

Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H et al (2013) Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. https://doi.org/10.1093/annonc/mds214 CrossRefPubMed

Paz-Ares L, Tan EH, O'Byrne K, Zhang L, Hirsh V, Boyer M et al (2017) Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-lung 7 trial. Ann Oncol. https://doi.org/10.1093/annonc/mdw611 CrossRefPubMedPubMedCentral

Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. https://doi.org/10.1056/nejmoa1606774 CrossRefPubMed

Li M, Zhang Q, Fu P, Li P, Peng A, Zhang G et al (2012) Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. PLoS ONE. https://doi.org/10.1371/journal.pone.0037229 CrossRefPubMedPubMedCentral

Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P et al (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. https://doi.org/10.1016/S1470-2045(12)70001-3 CrossRefPubMed

10.

Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P et al (2013) PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2012.47.1102 CrossRefPubMed

11.

Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL et al (1997) LY231514, a pyrrolo[2, 3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116–1123PubMed

12.

Gonen N, Assaraf YG (2012) Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Update. https://doi.org/10.1016/j.drup.2012.07.002 CrossRef

13.

Buque A, Aresti U, Calvo B, Sh Muhialdin J, Munoz A, Carrera S et al (2013) Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells. PLoS ONE. https://doi.org/10.1371/journal.pone.0063338 CrossRefPubMedPubMedCentral

14.

Chattopadhyay S, Moran RG, Goldman ID (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-06-0343 CrossRefPubMed

15.

Song L, Li W, Zhang H, Liao W, Dai T, Yu C et al (2009) Over-expression of AEG-1 significantly associates with tumour aggressiveness and poor prognosis in human non-small cell lung cancer. J Pathol. https://doi.org/10.1002/path.2595 CrossRefPubMed

16.

Yoo BK, Chen D, Su ZZ, Gredler R, Yoo J, Shah K et al (2010) Molecular mechanism of chemoresistance by astrocyte elevated gene-1. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-09-4009 CrossRefPubMedPubMedCentral

17.

Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB (2013) AEG-1/MTDH/LYRIC: signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res. https://doi.org/10.1016/B978-0-12-401676-7.00003-6 CrossRefPubMedPubMedCentral

18.

Bonanno L, Costa C, Majem M, Favaretto A, Rugge M, Rosell R (2013) The predictive value of BRCA1 and RAP80 mRNA expression in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy. Ann Oncol. https://doi.org/10.1093/annonc/mdt063 CrossRefPubMed

19.

Shen J, Wei J, Guan W, Wang H, Ding Y, Qian X et al (2014) Plasma mRNA expression levels of BRCA1 and TS as potential predictive biomarkers for chemotherapy in gastric cancer. J Transl Med. https://doi.org/10.1186/s12967-014-0355-2 CrossRefPubMedPubMedCentral

20.

Ceppi P, Rapa I, Lo Iacono M, Righi L, Giorcelli J, Pautasso M et al (2012) Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer. Int J Cancer. https://doi.org/10.1002/ijc.26188 CrossRefPubMed

21.

Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A et al (2006) Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. https://doi.org/10.1002/cncr.22208 CrossRefPubMed

22.

Liu Y, Yin TJ, Zhou R, Zhou S, Fan L, Zhang RG (2013) Expression of thymidylate synthase predicts clinical outcomes of pemetrexed-containing chemotherapy for non-small-cell lung cancer: a systemic review and meta-analysis. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-013-2299-2 CrossRefPubMedPubMedCentral

23.

Albertella MR, Lau A, O'Connor MJ (2005) The overexpression of specialized DNA polymerases in cancer. DNA Repair. https://doi.org/10.1016/j.dnarep.2005.01.005 CrossRefPubMed

24.

Cardona AF, Rojas L, Wills B, Arrieta O, Carranza H, Vargas C et al (2016) Pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab in hispanic patients with non-small cell lung cancer: ourcomes according to thymidylase synthase expression. PLoS ONE. https://doi.org/10.1371/journal.pone.0154293 CrossRefPubMedPubMedCentral

25.

Yang L, Shi T, Liu F, Ren C, Wang Z, Li Y et al (2015) REV3L, a promising target in regulating the chemosensitivity of cervical cancer cells. PLoS ONE. https://doi.org/10.1371/journal.pone.0120334 CrossRefPubMedPubMedCentral

26.

Lange SS, Takata K, Wood RD (2011) DNA polymerases and cancer. Nat Rev Cancer. https://doi.org/10.1038/nrc2998 CrossRefPubMedPubMedCentral

27.

Doles J, Oliver TG, Cameron ER, Hsu G, Jacks T, Walker GC et al (2010) Suppression of Rev3, the catalytic subunit of Pol{ ζ }, sensitizes drug-resistant lung tumors to chemotherapy. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1011409107 CrossRefPubMed

28.

Sharma S, Shah NA, Joiner AM, Roberts KH, Canman CE (2012) DNA polymerase ζ is a major determinant of resistance to platinum-based chemotherapeutic agents. Mol Pharmacol. https://doi.org/10.1124/mol.111.076828 CrossRefPubMedPubMedCentral

29.

Makarova AV, Burgers PM (2015) Eukaryotic DNA polymerase ζ. DNA Repair. https://doi.org/10.1016/j.dnarep.2015.02.012 CrossRefPubMedPubMedCentral

30.

Wittschieben JP, Patil V, Glushets V, Robinson LJ, Kusewitt DF, Wood RD (2010) Loss of DNA polymerase ζ enhances spontaneous tumorigenesis. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-09-4267 CrossRefPubMedPubMedCentral

31.

Brondello JM, Pillaire MJ, Rodriguez C, Gourraud PA, Selves J, Cazaux C et al (2008) Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol ζ. Oncogene. https://doi.org/10.1038/onc.2008.212 CrossRefPubMed

32.

Zhang S, Chen H, Zhao X, Cao J, Tong J, Lu J et al (2013) REV3L 3′UTR 460 T%3eC polymorphism in microRNA target sites contributes to lung cancer susceptibility. Oncogene. https://doi.org/10.1038/onc.2012.32 CrossRefPubMedPubMedCentral

33.

Wang W, Sheng W, Yu C, Cao J, Zhou J, Wu J et al (2015) REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells. Oncology Rep. https://doi.org/10.3892/or.2015.4121 CrossRef

34.

Zhang D, Ochi N, Takigawa N, Tanimoto Y, Chen Y, Ichihara E et al (2011) Establishment of pemetrexed-resistant non-small cell lung cancer cell lines. Cancer Lett. https://doi.org/10.1016/j.canlet.2011.06.006 CrossRefPubMedPubMedCentral

35.

Nicolson MC, Fennell DA, Ferry D, O'Byrne K, Shah R, Potter V et al (2013) Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial. J Thorac Oncol. https://doi.org/10.1097/JTO.0b013e318292c500 CrossRefPubMed

36.

Ozasa H, Oguri T, Uemura T, Miyazaki M, Maeno K, Sato S et al (2010) Significance of thymidylate synthase for resistance to pemetrexed in lung cancer. Cancer Sci. https://doi.org/10.1111/j.1349-7006.2009.01358.x CrossRefPubMed

37.

Chamizo C, Zazo S, Domine M, Cristobal I, Garcia-Foncillas J, Rojo F et al (2015) Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer. BMC Pulm Med. https://doi.org/10.1186/s12890-015-0132-x CrossRefPubMedPubMedCentral

38.

Yang M, Fan WF, Pu XL, Liu FY, Meng LJ, Wang J (2014) Significance of thymidylate synthase expression for resistance to pemetrexed in pulmonary adenocarcinoma. Oncology Lett. https://doi.org/10.3892/ol.2013.1688 CrossRef

Title: Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients
Authors: M. Teresa Agulló-Ortuño
Inmaculada García-Ruiz
C. Vanesa Díaz-García
Ana B. Enguita
Virginia Pardo-Marqués
Elena Prieto-García
Santiago Ponce
Lara Iglesias
Jon Zugazagoitia
José A. López-Martín
Luis Paz-Ares
Juan A. Nuñez
Publication date: 01-03-2020
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
NSCLC
Biomarkers
Cytostatic Therapy
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-04008-9

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