Mechanisms of Resistance to Chemotherapy in Non-small Cell Lung Cancer

Overview

Journal Arch Pharm Res

Specialty Pharmacology

Date 2021 Feb 20

PMID 33608812

Citations 50

Authors

Hye-Young Min

Ho-Young Lee

Affiliations

Soon will be listed here.

Abstract

Non-small cell lung cancer (NSCLC), which represents 80-85% of lung cancer cases, is one of the leading causes of human death worldwide. The majority of patients undergo an intensive and invasive treatment regimen, which may include radiotherapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these, depending on disease stage and performance status. Despite advances in therapeutic regimens, the 5-year survival of NSCLC is approximately 20-30%, largely due to diagnosis at advanced stages. Conventional chemotherapy is still the standard treatment option for patients with NSCLC, especially those with advanced disease. However, the emergence of resistance to chemotherapeutic agents (chemoresistance) poses a significant obstacle to the management of patients with NSCLC. Therefore, to develop efficacious chemotherapeutic approaches for NSCLC, it is necessary to understand the mechanisms underlying chemoresistance. Several mechanisms are known to mediate chemoresistance. These include altered cellular targets for chemotherapy, decreased cellular drug concentrations, blockade of chemotherapy-induced cell cycle arrest and apoptosis, acquisition of epithelial-mesenchymal transition and cancer stem cell-like phenotypes, deregulated expression of microRNAs, epigenetic modulation, and the interaction with tumor microenvironments. In this review, we summarize the mechanisms underlying chemoresistance and tumor recurrence in NSCLC and discuss potential strategies to avoid or overcome chemoresistance.

Citing Articles

Exploring miR-21 Knock-Out Using CRISPR/Cas as a Treatment for Lung Cancer.

Lara P, Aguilar-Gonzalez A, Martin F, Mesas C, Moreno J, Rama A Genes (Basel). 2025; 16(2).

PMID: 40004462 PMC: 11855122. DOI: 10.3390/genes16020133.

Selective inhibition of TGF-β-induced epithelial-mesenchymal transition overcomes chemotherapy resistance in high-risk lung squamous cell carcinoma.

Sun L, Wang J, Yu H, Zhu X, Zhang J, Hu J Commun Biol. 2025; 8(1):152.

PMID: 39893253 PMC: 11787392. DOI: 10.1038/s42003-025-07595-x.

Application of nanomaterials in precision treatment of lung cancer.

Zhang C, Fan J, Wu L iScience. 2025; 28(1):111704.

PMID: 39886464 PMC: 11780121. DOI: 10.1016/j.isci.2024.111704.

The crosstalk between SND1 and PDCD4 is associated with chemoresistance of non-small cell lung carcinoma cells.

Zhao Y, Dhani S, Gogvadze V, Zhivotovsky B Cell Death Discov. 2025; 11(1):34.

PMID: 39885142 PMC: 11782486. DOI: 10.1038/s41420-025-02310-5.

[Application of Nano-drug Delivery Technology in Overcoming Drug Resistance  in Lung Cancer].

Lu Y, Wang C, Liu B Zhongguo Fei Ai Za Zhi. 2025; 27(11):864-872.

PMID: 39800482 PMC: 11732387. DOI: 10.3779/j.issn.1009-3419.2024.101.30.

References

Achiwa H, Oguri T, Sato S, Maeda H, Niimi T, Ueda R . Determinants of sensitivity and resistance to gemcitabine: the roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non-small cell lung cancer. Cancer Sci. 2004; 95(9):753-7. PMC: 11158492. DOI: 10.1111/j.1349-7006.2004.tb03257.x. View

Adjei A, Salavaggione O, Mandrekar S, Dy G, Allen Ziegler K, Endo C . Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. J Thorac Oncol. 2010; 5(9):1346-53. PMC: 5735419. DOI: 10.1097/JTO.0b013e3181ec18c4. View

Aguirre-Ghiso J . Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007; 7(11):834-46. PMC: 2519109. DOI: 10.1038/nrc2256. View

Ahmad A, Maitah M, Ginnebaugh K, Li Y, Bao B, Gadgeel S . Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs. J Hematol Oncol. 2013; 6(1):77. PMC: 3852827. DOI: 10.1186/1756-8722-6-77. View

Albertella M, Green C, Lehmann A, OConnor M . A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res. 2005; 65(21):9799-806. DOI: 10.1158/0008-5472.CAN-05-1095. View

Arevalo E, Castanon E, Lopez I, Salgado J, Collado V, Santisteban M . Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed. J Transl Med. 2014; 12:98. PMC: 3996904. DOI: 10.1186/1479-5876-12-98. View

Atjanasuppat K, Lirdprapamongkol K, Jantaree P, Svasti J . Non-adherent culture induces paclitaxel resistance in H460 lung cancer cells via ERK-mediated up-regulation of βIVa-tubulin. Biochem Biophys Res Commun. 2015; 466(3):493-8. DOI: 10.1016/j.bbrc.2015.09.057. View

Bai L, Zhu R, Chen Z, Gao L, Zhang X, Wang X . Potential role of short hairpin RNA targeting epidermal growth factor receptor in growth and sensitivity to drugs of human lung adenocarcinoma cells. Biochem Pharmacol. 2006; 71(8):1265-71. DOI: 10.1016/j.bcp.2005.12.029. View

Barr M, Gray S, Hoffmann A, Hilger R, Thomale J, OFlaherty J . Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One. 2013; 8(1):e54193. PMC: 3547914. DOI: 10.1371/journal.pone.0054193. View

10.

Basu A, Broyde S, Iwai S, Kisker C . DNA damage, mutagenesis, and DNA repair. J Nucleic Acids. 2011; 2010:182894. PMC: 3014688. DOI: 10.4061/2010/182894. View

11.

Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A . RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006; 24(29):4731-7. DOI: 10.1200/JCO.2006.06.1101. View

12.

Scherpereel A, Opitz I, Berghmans T, Psallidas I, Glatzer M, Rigau D . ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma. Eur Respir J. 2020; 55(6). DOI: 10.1183/13993003.00953-2019. View

13.

Bessho Y, Oguri T, Ozasa H, Uemura T, Sakamoto H, Miyazaki M . ABCC10/MRP7 is associated with vinorelbine resistance in non-small cell lung cancer. Oncol Rep. 2008; 21(1):263-8. View

14.

Booton R, Ward T, Ashcroft L, Morris J, Heighway J, Thatcher N . ERCC1 mRNA expression is not associated with response and survival after platinum-based chemotherapy regimens in advanced non-small cell lung cancer. J Thorac Oncol. 2007; 2(10):902-6. DOI: 10.1097/JTO.0b013e318155a637. View

15.

Boukovinas I, Papadaki C, Mendez P, Taron M, Mavroudis D, Koutsopoulos A . Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients. PLoS One. 2008; 3(11):e3695. PMC: 2579656. DOI: 10.1371/journal.pone.0003695. View

16.

Catuogno S, Cerchia L, Romano G, Pognonec P, Condorelli G, de Franciscis V . miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene. 2012; 32(3):341-51. DOI: 10.1038/onc.2012.51. View

17.

Ceppi P, Novello S, Cambieri A, Longo M, Monica V, Lo Iacono M . Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2009; 15(3):1039-45. DOI: 10.1158/1078-0432.CCR-08-1227. View

18.

Ceppi P, Rapa I, Lo Iacono M, Righi L, Giorcelli J, Pautasso M . Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer. Int J Cancer. 2011; 130(8):1777-86. DOI: 10.1002/ijc.26188. View

19.

Chatterjee A, Chattopadhyay D, Chakrabarti G . miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS One. 2014; 9(4):e95716. PMC: 3995800. DOI: 10.1371/journal.pone.0095716. View

20.

Chatterjee A, Chattopadhyay D, Chakrabarti G . MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis. Cell Signal. 2014; 27(2):189-203. DOI: 10.1016/j.cellsig.2014.11.023. View