Understanding and Targeting the Epigenetic Regulation to Overcome
EGFR-TKIs Resistance in Human Cancer

Lan      Sun; Lingyue      Gao; Yingxi      Zhao; Yuqing      Wang; Qianhui      Xu; Yiru      Zheng; Jiali      Chen; He      Wang; Lihui      Wang

doi:10.2174/1574892818666221201145810

Abstract

Background: The occurrence and progression of cancer are the results of the dysregulation of genetics and epigenetics. Epigenetic regulation can reversibly affect gene transcription activity without changing DNA structure. Covalent modification of histones is crucial in the epigenetic regulation of gene expression. Furthermore, epidermal growth factor receptor (EGFR) significantly affects cell tumorigenesis, proliferation, antitumor drug resistance, etc. Overexpression of EGFR promotes cancer development. Therefore, EGFR-targeted drugs have become the focus of tumor therapy. With the advent of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), EGFR-TKIs resistance, which occurs about half a year to a year, has become an obstacle in cancer treatment.

Objective: The objective of this study is to discuss the ways to overcome EGFR-TKIs resistance in a variety of tumors.

Methods: The combination therapy of epigenetic drugs and other drugs is used.

Results: The combination of the two drugs can overcome the resistance of EGFR-TKIs and prolong the survival of patients.

Conclusion: This article depicts the concepts of epigenetics and the mechanism of EGFR-TKIs resistance and then illustrates the relationship between epigenetic mechanisms and EGFR-TKIs resistance. Finally, it discusses the clinical research and the latest patents for using epigenetic drugs to reverse EGFR-TKIs resistance in human cancer. In the future, more novel targets may be discovered for overcoming resistance to EGFR-TKIs, not just on histone deacetylases (HDACs). The dosing course and mode of administration of the combination therapy containing epigenetic drugs need further study. This review provides new ideas for using epigenetic agents to overcome EGFR-TKIs resistance.

Keywords: Epigenetic regulation, EGFR-TKIs, cancer, resistant mechanisms, patent, clinical trials, combination therapy.

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[1]
Moehler M, Maderer A, Ehrlich A, et al. Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: An open-label, phase I trial with an extensive biomarker program. BMC Cancer  2019; 19(1): 55.
 [http://dx.doi.org/10.1186/s12885-018-5223-7] [PMID: 30634942]

[2]
Spaans JN, Goss GD. Epidermal growth factor receptor tyrosine kinase inhibitors in early-stage nonsmall cell lung cancer. Curr Opin Oncol  2015; 27(2): 102-7.
 [http://dx.doi.org/10.1097/CCO.0000000000000163] [PMID: 25611026]

[3]
Hayashi H, Nakagawa K. Is EGF receptor-tyrosine kinase inhibitor therapy in non-small-cell lung cancer patients with EGFR mutations the best option? Lung Cancer Manag  2013; 2(6): 441-3.
 [http://dx.doi.org/10.2217/lmt.13.57]

[4]
Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med  2013; 19(11): 1389-400.
 [http://dx.doi.org/10.1038/nm.3388] [PMID: 24202392]

[5]
Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer  2018; 17(1): 38.
 [http://dx.doi.org/10.1186/s12943-018-0777-1] [PMID: 29455650]

[6]
Sandoval J, Esteller M. Cancer epigenomics: Beyond genomics. Curr Opin Genet Dev  2012; 22(1): 50-5.
 [http://dx.doi.org/10.1016/j.gde.2012.02.008] [PMID: 22402447]

[7]
Taby R, Issa JPJ. Cancer epigenetics. CA Cancer J Clin  2010; 60(6): 376-92.
 [http://dx.doi.org/10.3322/caac.20085] [PMID: 20959400]

[8]
Fabbri M, Calin GA. Epigenetics and miRNAs in human cancer. Adv Genet  2010; 70: 87-99.
 [http://dx.doi.org/10.1016/B978-0-12-380866-0.60004-6] [PMID: 20920746]

[9]
Schiffmann I, Greve G, Jung M, Lübbert M. Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives. Epigenetics  2016; 11(12): 858-70.
 [http://dx.doi.org/10.1080/15592294.2016.1237345] [PMID: 27846368]

[10]
Wu YS, Lee ZY, Chuah LH, Mai CW, Ngai SC. Epigenetics in metastatic breast cancer: Its regulation and implications in diagnosis, prognosis and therapeutics. Curr Cancer Drug Targets  2019; 19(2): 82-100.
 [http://dx.doi.org/10.2174/1568009618666180430130248] [PMID: 29714144]

[11]
Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology  2013; 38(1): 23-38.
 [http://dx.doi.org/10.1038/npp.2012.112] [PMID: 22781841]

[12]
Ning B, Li W, Zhao W, Wang R. Targeting epigenetic regulations in cancer. Acta Biochim Biophys Sin  2016; 48(1): 97-109.
 [http://dx.doi.org/10.1093/abbs/gmv116] [PMID: 26508480]

[13]
Altenberger C, Heller G, Ziegler B, et al. SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers. Mol Cancer  2017; 16(1): 1.
 [http://dx.doi.org/10.1186/s12943-016-0568-5] [PMID: 28093071]

[14]
Eisenberg-Lerner A, Kimchi A. DAPk silencing by DNA methylation conveys resistance to anti EGFR drugs in lung cancer cells. Cell Cycle  2012; 11(11): 2051.
 [http://dx.doi.org/10.4161/cc.20538] [PMID: 22622084]

[15]
Maeda M, Murakami Y, Watari K, Kuwano M, Izumi H, Ono M. CpG hypermethylation contributes to decreased expression of PTEN during acquired resistance to gefitinib in human lung cancer cell lines. Lung Cancer  2015; 87(3): 265-71.
 [http://dx.doi.org/10.1016/j.lungcan.2015.01.009] [PMID: 25638724]

[16]
Musselman CA, Gibson MD, Hartwick EW, et al. Binding of PHF1 Tudor to H3K36me3 enhances nucleosome accessibility. Nat Commun  2013; 4(1): 2969.
 [http://dx.doi.org/10.1038/ncomms3969] [PMID: 24352064]

[17]
Bassett S, Barnett M. The role of dietary Histone Deacetylases (HDACs) inhibitors in health and disease. Nutrients  2014; 6(10): 4273-301.
 [http://dx.doi.org/10.3390/nu6104273] [PMID: 25322459]

[18]
Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci  2017; 18(7): 1414.
 [http://dx.doi.org/10.3390/ijms18071414] [PMID: 28671573]

[19]
Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Genome Biol  2019; 20(1): 245.
 [http://dx.doi.org/10.1186/s13059-019-1870-5] [PMID: 31747960]

[20]
Moreno-Yruela C, Bæk M, Vrsanova AE, Schulte C, Maric HM, Olsen CA. Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases. Nat Commun  2021; 12(1): 62.
 [http://dx.doi.org/10.1038/s41467-020-20250-9] [PMID: 33397936]

[21]
Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med  2016; 6(10): a026831.
 [http://dx.doi.org/10.1101/cshperspect.a026831] [PMID: 27599530]

[22]
Peng X, Li L, Chen J, et al. Discovery of novel histone deacetylase 6 (HDAC6) inhibitors with enhanced antitumor immunity of anti-PD-L1 immunotherapy in melanoma. J Med Chem  2022; 65(3): 2434-57.
 [http://dx.doi.org/10.1021/acs.jmedchem.1c01863] [PMID: 35043615]

[23]
Edwards A, Li J, Atadja P, Bhalla K, Haura EB. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells. Mol Cancer Ther  2007; 6(9): 2515-24.
 [http://dx.doi.org/10.1158/1535-7163.MCT-06-0761] [PMID: 17876048]

[24]
Witta SE, Gemmill RM, Hirsch FR, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res  2006; 66(2): 944-50.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-1988] [PMID: 16424029]

[25]
Lin YC, Lin YC, Shih JY, et al. DUSP1 expression induced by HDAC1 inhibition mediates gefitinib sensitivity in non-small cell lung cancers. Clin Cancer Res  2015; 21(2): 428-38.
 [http://dx.doi.org/10.1158/1078-0432.CCR-14-1150] [PMID: 25593344]

[26]
Weng CH, Chen LY, Lin YC, et al. Epithelial-Mesenchymal Transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene  2019; 38(4): 455-68.
 [http://dx.doi.org/10.1038/s41388-018-0454-2] [PMID: 30111817]

[27]
Lu Y, Liu Y, Oeck S, Glazer PM. Hypoxia promotes resistance to EGFR inhibition in NSCLC cells via the histone demethylases, LSD1 and PLU-1. Mol Cancer Res  2018; 16(10): 1458-69.
 [http://dx.doi.org/10.1158/1541-7786.MCR-17-0637] [PMID: 29934325]

[28]
Watson ZL, Yamamoto TM, McMellen A, et al. Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma. Clin Epigenetics  2019; 11(1): 165.
 [http://dx.doi.org/10.1186/s13148-019-0758-2] [PMID: 31775874]

[29]
Wang L, Dong X, Ren Y, et al. Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway. Cell Death Dis  2018; 9(2): 129.
 [http://dx.doi.org/10.1038/s41419-017-0120-6] [PMID: 29374157]

[30]
Duan R, Du W, Guo W. EZH2: A novel target for cancer treatment. J Hematol Oncol  2020; 13(1): 104.
 [http://dx.doi.org/10.1186/s13045-020-00937-8] [PMID: 32723346]

[31]
Zhang N, Li Y, Zheng Y, et al. miR-608 and miR-4513 significantly contribute to the prognosis of lung adenocarcinoma treated with EGFR-TKIs. Lab Invest  2019; 99(4): 568-76.
 [http://dx.doi.org/10.1038/s41374-018-0164-y] [PMID: 30552364]

[32]
Amri J, Molaee N, Karami H. Up-regulation of MiRNA-125a-5p inhibits cell proliferation and increases EGFR-TKI induced apoptosis in lung cancer cells. Asian Pac J Cancer Prev  2019; 20(11): 3361-7.
 [http://dx.doi.org/10.31557/APJCP.2019.20.11.3361] [PMID: 31759360]

[33]
Zhao Q, Li P, Ma J, Yu X. MicroRNAs in lung cancer and lung cancer bone metastases: Biomarkers for early diagnosis and targets for treatment. Recent Patents Anticancer Drug Discov  2015; 10(2): 182-200.
 [http://dx.doi.org/10.2174/1574892810666150120163617] [PMID: 25600282]

[34]
Markou A, Zavridou M, Lianidou ES. miRNA-21 as a novel therapeutic target in lung cancer. Lung Cancer  2016; 7: 19-27.
 [PMID: 28210157]

[35]
Shen H, Zhu F, Liu J, et al. Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS One  2014; 9(7): e103305.
 [http://dx.doi.org/10.1371/journal.pone.0103305] [PMID: 25058005]

[36]
Li B, Ren S, Li X, et al. MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer  2014; 83(2): 146-53.
 [http://dx.doi.org/10.1016/j.lungcan.2013.11.003] [PMID: 24331411]

[37]
Liu YN, Tsai MF, Wu SG, et al. miR-146b-5p enhances the sensitivity of NSCLC to EGFR tyrosine kinase inhibitors by regulating the IRAK1/NF-κB pathway. Mol Ther Nucleic Acids  2020; 22: 471-83.
 [http://dx.doi.org/10.1016/j.omtn.2020.09.015] [PMID: 33230450]

[38]
Ma P, Zhang M, Nie F, et al. Transcriptome analysis of EGFR tyrosine kinase inhibitors resistance associated long noncoding RNA in non-small cell lung cancer. Biomed Pharmacother  2017; 87: 20-6.
 [http://dx.doi.org/10.1016/j.biopha.2016.12.079] [PMID: 28040594]

[39]
Zhou JY, Chen X, Zhao J, et al. MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. Cancer Lett  2014; 351(2): 265-71.
 [http://dx.doi.org/10.1016/j.canlet.2014.06.010] [PMID: 24983493]

[40]
Chen J, Cui J, Guo X, Cao X, Li Q. Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1. Cancer Med  2018; 7(4): 1394-403.
 [http://dx.doi.org/10.1002/cam4.1326] [PMID: 29493886]

[41]
Yue J, Lv D, Wang C, et al. Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin β3. Oncogene  2018; 37(31): 4300-12.
 [http://dx.doi.org/10.1038/s41388-018-0276-2] [PMID: 29717264]

[42]
Wang HY, Liu YN, Wu SG, et al. MiR-200c-3p suppression is associated with development of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer via a mediating epithelial-to-mesenchymal transition (EMT) process. Cancer Biomark  2020; 28(3): 351-63.
 [http://dx.doi.org/10.3233/CBM-191119] [PMID: 32417760]

[43]
Han S, Lin F, Ruan Y, et al. miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-κB pathway. Int Immunopharmacol  2021; 99: 108022.
 [http://dx.doi.org/10.1016/j.intimp.2021.108022] [PMID: 34339961]

[44]
Yin J, Hu W, Pan L, et al. let 7 and miR 17 promote self renewal and drive gefitinib resistance in non small cell lung cancer. Oncol Rep  2019; 42(2): 495-508.
 [http://dx.doi.org/10.3892/or.2019.7197] [PMID: 31233201]

[45]
Liu X, Jiang T, Li X, et al. Exosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway. J Cell Mol Med  2020; 24(2): 1529-40.
 [http://dx.doi.org/10.1111/jcmm.14838] [PMID: 31894895]

[46]
Zhou J, Wang J, Zeng Y, et al. Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer. Oncotarget  2015; 6(42): 44332-45.
 [http://dx.doi.org/10.18632/oncotarget.6293] [PMID: 26554308]

[47]
Hassanein SS, Ibrahim SA, Abdel-Mawgood AL. Cell behavior of non-small cell lung cancer is at EGFR and MicroRNAs hands. Int J Mol Sci  2021; 22(22): 12496.
 [http://dx.doi.org/10.3390/ijms222212496] [PMID: 34830377]

[48]
Mercer TR, Mattick JS. Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol  2013; 20(3): 300-7.
 [http://dx.doi.org/10.1038/nsmb.2480] [PMID: 23463315]

[49]
Jiang W, Xia J, Xie S, et al. Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs. Drug Resist Updat  2020; 50: 100683.
 [http://dx.doi.org/10.1016/j.drup.2020.100683] [PMID: 32146422]

[50]
Sun R, Wang R, Chang S, et al. Long non-coding RNA in drug resistance of non-small cell lung cancer: A mini review. Front Pharmacol  2019; 10: 1457.
 [http://dx.doi.org/10.3389/fphar.2019.01457] [PMID: 31920650]

[51]
Wang L, Ma L, Xu F, et al. Role of long non-coding RNA in drug resistance in non-small cell lung cancer. Thorac Cancer  2018; 9(7): 761-8.
 [http://dx.doi.org/10.1111/1759-7714.12652] [PMID: 29726094]

[52]
Yang H, Fu H, Xu W, Zhang X. Exosomal non-coding RNAs: A promising cancer biomarker. Clinic Chem Lab Med (CCLM) 2016; 54(12): 1871-9. 

[53]
Li Q, Shao Y, Zhang X, et al. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. Tumour Biol  2015; 36(3): 2007-12.
 [http://dx.doi.org/10.1007/s13277-014-2807-y] [PMID: 25391424]

[54]
Liu Y, Xu N, Liu B, et al. Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines. Oncotarget  2016; 7(28): 43835-51.
 [http://dx.doi.org/10.18632/oncotarget.9699] [PMID: 27270310]

[55]
Shu D, Xu Y, Chen W. Knockdown of lncRNA BLACAT1 reverses the resistance of afatinib to non-small cell lung cancer via modulating STAT3 signalling. J Drug Target  2020; 28(3): 300-6.
 [http://dx.doi.org/10.1080/1061186X.2019.1650368] [PMID: 31359792]

[56]
Wang Q, Li X, Ren S, et al. HOTAIR induces EGFR-TKIs resistance in non-small cell lung cancer through epithelial-mesenchymal transition. Lung Cancer  2020; 147: 99-105.
 [http://dx.doi.org/10.1016/j.lungcan.2020.06.037] [PMID: 32683208]

[57]
Pan H, Jiang T, Cheng N, et al. Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer. Oncotarget  2016; 7(31): 49948-60.
 [http://dx.doi.org/10.18632/oncotarget.10521] [PMID: 27409677]

[58]
Peng W-X, Koirala P, Mo Y-Y. LncRNA-mediated regulation of cell signaling in cancer. Oncogene  2017; 36(41): 5661-7.
 [http://dx.doi.org/10.1038/onc.2017.184] [PMID: 28604750]

[59]
Wang B, Jiang H, Wang L, et al. Increased MIR31HG lncRNA expression increases gefitinib resistance in non-small cell lung cancer cell lines through the EGFR/PI3K/AKT signaling pathway. Oncol Lett  2017; 13(5): 3494-500.
 [http://dx.doi.org/10.3892/ol.2017.5878] [PMID: 28529576]

[60]
Chen Z, Chen Q, Cheng Z, et al. Long non-coding RNA CASC9 promotes gefitinib resistance in NSCLC by epigenetic repression of DUSP1. Cell Death Dis  2020; 11(10): 858.
 [http://dx.doi.org/10.1038/s41419-020-03047-y] [PMID: 33056982]

[61]
Yi YC, Chen XY, Zhang J, Zhu JS. Novel insights into the interplay between m6A modification and noncoding RNAs in cancer. Mol Cancer  2020; 19(1): 121.
 [http://dx.doi.org/10.1186/s12943-020-01233-2] [PMID: 32767982]

[62]
Zhou H, Mao L, Xu H, Wang S, Tian J. The functional roles of m6A modification in T lymphocyte responses and autoimmune diseases. Cytokine Growth Factor Rev  2022; 65: 51-60.
 [http://dx.doi.org/10.1016/j.cytogfr.2022.04.004] [PMID: 35490098]

[63]
Liu S, Li Q, Li G, et al. The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene. Cell Death Dis  2020; 11(11): 969.
 [http://dx.doi.org/10.1038/s41419-020-03148-8] [PMID: 33177491]

[64]
Bauman J, Verschraegen C, Belinsky S, et al. A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies. Cancer Chemother Pharmacol  2012; 69(2): 547-54.
 [http://dx.doi.org/10.1007/s00280-011-1729-2] [PMID: 21901396]

[65]
Gerber DE, Boothman DA, Fattah FJ, et al. Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer. Lung Cancer  2015; 90(3): 534-41.
 [http://dx.doi.org/10.1016/j.lungcan.2015.10.008] [PMID: 26474959]

[66]
Han JY, Lee SH, Lee GK, et al. Phase I/II study of gefitinib (Iressa®) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol  2015; 75(3): 475-83.
 [http://dx.doi.org/10.1007/s00280-014-2664-9] [PMID: 25552401]

[67]
Reguart N, Rosell R, Cardenal F, et al. Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. Lung Cancer  2014; 84(2): 161-7.
 [http://dx.doi.org/10.1016/j.lungcan.2014.02.011] [PMID: 24636848]

[68]
Liao C, Tian Y, Xie Z, Lyu X. Phthalazine derivative, preparation method and applications thereof. CN110845425, 2020. 

[69]
Marcar L, Bardhan K, Gheorghiu L, et al. Acquired resistance of EGFR-mutated lung cancer to tyrosine kinase inhibitor treatment promotes PARP inhibitor sensitivity. Cell Rep  2019; 27(12): 3422-32.
 [http://dx.doi.org/10.1016/j.celrep.2019.05.058] [PMID: 31216465]

[70]
Gan Z, Yu Y, Pan T. HDAC/ALK double-target inhibitor and preparation method and application thereof. Patent CN111039875, 2020. 

[71]
Umapathy G, Mendoza-Garcia P, Hallberg B, Palmer RH. Targeting anaplastic lymphoma kinase in neuroblastoma. APMIS. Acta pathologica, microbiologica, et immunologica Scandinavica  2019; 127(5): 288-302.
 [http://dx.doi.org/10.1111/apm.12940]

[72]
De Mello RA, Liu DJ, Aguiar PN. Recent Patents Anticancer Drug Discov  2016; 11(4): 393-400.
 [http://dx.doi.org/10.2174/1574892811666160803090944]

[73]
Greg P. Methods to increase the sensitivity and reversing the resistance to drugs Patent WO2021055562, 2021.

[74]
Cao B, Ma S, Lang J, Zhu G, Mi K. Verification method for reason for EREG to promote NSCLC cells to generate drug resistance to EGFR-TKI Patent CN112813164, 2021.

[75]
Chikao M, Kei O, Ryo H, Takumi I, Yutaro K. Agent for reversing resistance to anticancer drugs Patent WO2021251340, 2021.

[76]
Stephen B, Drew M, Suzanne L. Cancer therapy via a combination of epigenetic modulation and immune modulation Patent US2021161928, 2021.

[77]
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med  2019; 380(12): 1103-15.
 [http://dx.doi.org/10.1056/NEJMoa1816047] [PMID: 30779531]

[78]
Peng X, Wang Z, Liu Y, et al. Oxyfadichalcone C inhibits melanoma A375 cell proliferation and metastasis via suppressing PI3K/Akt and MAPK/ERK pathways. Life Sci  2018; 206: 35-44.
 [http://dx.doi.org/10.1016/j.lfs.2018.05.032] [PMID: 29782872]

[79]
Kelly AD, Issa JPJ. The promise of epigenetic therapy: Reprogramming the cancer epigenome. Curr Opin Genet Dev  2017; 42: 68-77.
 [http://dx.doi.org/10.1016/j.gde.2017.03.015] [PMID: 28412585]

[80]
Kim YD, Park SM, Ha HC, et al. HDAC inhibitor, CG-745, enhances the anti-cancer effect of anti-PD-1 immune checkpoint inhibitor by modulation of the immune microenvironment. J Cancer  2020; 11(14): 4059-72.
 [http://dx.doi.org/10.7150/jca.44622] [PMID: 32368288]

[81]
Isomoto K, Haratani K, Hayashi H, et al. Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation–positive non-small cell lung cancer. Clin Cancer Res  2020; 26(8): 2037-46.
 [http://dx.doi.org/10.1158/1078-0432.CCR-19-2027] [PMID: 31937613]

[82]
Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet  2019; 51(2): 202-6.
 [http://dx.doi.org/10.1038/s41588-018-0312-8] [PMID: 30643254]

[83]
Yang L, Hao X, Hu X, et al. Superior efficacy of immunotherapy‐based combinations over monotherapy forEGFR mutant non‐small cell lung cancer acquired resistance to EGFR‐TKIs. Thorac Cancer  2020; 11(12): 3501-9.
 [http://dx.doi.org/10.1111/1759-7714.13689] [PMID: 33075201]

[84]
Wiest N, Majeed U, Seegobin K, Zhao Y, Lou Y, Manochakian R. Role of immune checkpoint inhibitor therapy in advanced EGFR-mutant non-small cell lung cancer. Front Oncol  2021; 11: 751209.
 [http://dx.doi.org/10.3389/fonc.2021.751209] [PMID: 34868953]

[85]
Vilgelm AE, Johnson DB, Richmond A. Combinatorial approach to cancer immunotherapy: Strength in numbers. J Leukoc Biol  2016; 100(2): 275-90.
 [http://dx.doi.org/10.1189/jlb.5RI0116-013RR] [PMID: 27256570]

[86]
Patel SA, Minn AJ. Combination cancer therapy with immune checkpoint blockade: Mechanisms and strategies. Immunity  2018; 48(3): 417-33.
 [http://dx.doi.org/10.1016/j.immuni.2018.03.007] [PMID: 29562193]

[87]
Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol  2019; 30(5): 839-44.
 [http://dx.doi.org/10.1093/annonc/mdz077] [PMID: 30847464]

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DOI https://dx.doi.org/10.2174/1574892818666221201145810	Print ISSN 1574-8928
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