The Anti-Tumor Activity of Afatinib in Pancreatic Ductal Adenocarcinoma Cells

Author(s): Zhenyu Ye, Yecheng Li, Jiaming Xie, Zhenyu Feng, Xiaodong Yang, Yong Wu, Kui Zhao, Yuwei Pu, Xiangrong Xu, Zhaobi Zhu, Wei Li, Jun Pan, Wei Chen*, Chungen Xing*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 12 , 2020

DOI : 10.2174/1871520620666200508090515

  Journal Home
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer and leading causes of pancreatic cancer death because of most PDAC patients with advanced unresectable disease at that time, which is remarkably resistant to all forms of chemotherapy and radiotherapy.

Objective: PDAC increases the social and patient's family burden. However, the PDAC pathogenesis is not identified. We are trying to uncover the underlying mechanism in the future.

Methods: In our research, the drug-resistant cell line was successfully induced in the vitro by progressive concentrations of Afatinib, which we named it as BxPC3-AR.

Results: It has been observed that the effect of autophagy was on the resistance of BxPC3-AR to Afatinib.

Conclusion: It has been confirmed that autophagy plays a certain role in BxPC3-AR resistance to Afatinib. Our findings provide a new perspective on the role of autophagy in pancreatic ductal adenocarcinoma.

Keywords: PDAC, afatinib, BxPC3-AR, BXPC3-PA, autophagy, poor prognosis.

[1]
González-Borja, I.; Viúdez, A.; Goñi, S.; Santamaria, E.; Carrasco-García, E.; Pérez-Sanz, J.; Hernández-García, I.; Sala-Elarre, P.; Arrazubi, V.; Oyaga-Iriarte, E.; Zárate, R.; Arévalo, S.; Sayar, O.; Vera, R.; Fernández-Irigoyen, J. Omics approaches in pancreatic adenocarcinoma. Cancers (Basel), 2019, 11(8), E1052.
[http://dx.doi.org/10.3390/cancers11081052] [PMID: 31349663]
[2]
Shinde, R.S.; Bhandare, M.; Chaudhari, V.; Shrikhande, S.V. Cutting-edge strategies for borderline resectable pancreatic cancer. Ann. Gastroenterol. Surg., 2019, 3(4), 368-372.
[http://dx.doi.org/10.1002/ags3.12254] [PMID: 31346575]
[3]
Lanfredini, S.; Thapa, A. RAS in pancreatic cancer. Biochem. Soc. Trans., 2019, 47(4), 961-972.
[4]
Hua, X.; Sun, Y.; Chen, J.; Wu, Y.; Sha, J.; Han, S.; Zhu, X. Circular RNAs in drug resistant tumors. Biomed. Pharmacother., 2019, 118, 109233.
[http://dx.doi.org/10.1016/j.biopha.2019.109233] [PMID: 31351436]
[5]
Lowrence, R.C.; Subramaniapillai, S.G.; Ulaganathan, V.; Nagarajan, S. Tackling drug resistance with efflux pump inhibitors: From bacteria to cancerous cells. Crit. Rev. Microbiol., 2019, 45(3), 334-353.
[http://dx.doi.org/10.1080/1040841X.2019.1607248]] [PMID: 31248314]
[6]
Follini, E.; Marchesini, M.; Roti, G. Strategies to overcome resistance mechanisms in T-cell acute lymphoblastic leukemia. Int. J. Mol. Sci., 2019, 20(12), E3021.
[http://dx.doi.org/10.3390/ijms20123021] [PMID: 31226848]
[7]
Zhou, L.; Ren, Y.; Wang, X.; Miao, D.; Lizaso, A.; Li, H.; Han-Zhang, H.; Qian, J.; Yang, H. Efficacy of afatinib in a HER2 amplification-positive endometrioid adenocarcinoma patient- a case report. OncoTargets Ther., 2019, 12, 5305-5309.
[http://dx.doi.org/10.2147/OTT.S206732] [PMID: 31308701]
[8]
Huguet, F.; Fernet, M.; Giocanti, N.; Favaudon, V.; Larsen, A.K. Afatinib, an irreversible EGFR family inhibitor, shows activity toward pancreatic cancer cells, alone and in combination with radiotherapy, independent of KRAS status. Target. Oncol., 2016, 11(3), 371-381.
[http://dx.doi.org/10.1007/s11523-015-0403-8] [PMID: 26668065]
[9]
Zeng, C.; Zhang, Z.; Wang, J. Application of the high-throughput TAB-array for the discovery of novel 5-hydroxymethylcytosine biomarkers in pancreatic ductal adenocarcinoma. Epigenomes, 2019, 3(3), 16.
[10]
Nissim, S.; Leshchiner, I.; Mancias, J.D.; Greenblatt, M.B.; Maertens, O.; Cassa, C.A.; Rosenfeld, J.A.; Cox, A.G.; Hedgepeth, J.; Wucherpfennig, J.I.; Kim, A.J.; Henderson, J.E.; Gonyo, P.; Brandt, A.; Lorimer, E.; Unger, B.; Prokop, J.W.; Heidel, J.R.; Wang, X.X.; Ukaegbu, C.I.; Jennings, B.C.; Paulo, J.A.; Gableske, S.; Fierke, C.A.; Getz, G.; Sunyaev, S.R.; Wade Harper, J.; Cichowski, K.; Kimmelman, A.C.; Houvras, Y.; Syngal, S.; Williams, C.; Goessling, W. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat. Genet., 2019, 51(9), 1308-1314.
[http://dx.doi.org/10.1038/s41588-019-0475-y] [PMID: 31406347]
[11]
Yoshioka, T.; Shien, K.; Takeda, T.; Takahashi, Y.; Kurihara, E.; Ogoshi, Y.; Namba, K.; Torigoe, H.; Sato, H.; Tomida, S.; Yamamoto, H.; Soh, J.; Fujiwara, T.; Toyooka, S. Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells. Cancer Sci., 2019, 110(8), 2549-2557.
[PMID: 31162771]
[12]
Tan, Y.N.; Cao, K.N.; Ren, G.H. Effects of the ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of afatinib in healthy Chinese volunteers. Xenobiotica, 2020, 50(2), 237-243.
[13]
Chen, Z.; Chen, Z.; Liu, Z.; Zhang, M. EPHA2 blockade reverses acquired resistance to afatinib induced by EPHA2-mediated MAPK pathway activation in gastric cancer cells and avatar mice. Int. J. Cancer, 2019, 145(9), 2440-2449.
[http://dx.doi.org/10.1002/ijc.32313] [PMID: 30957241]
[14]
Chen, M.; Zhuang, C.; Liu, Y.; Li, J.; Dai, F.; Xia, M.; Zhan, Y.; Lin, J.; Chen, Z.; He, A.; Xu, W.; Zhao, G.; Guo, Y.; Cai, Z.; Huang, W. Tetracycline-inducible shRNA targeting antisense long non-coding RNA HIF1A-AS2 represses the malignant phenotypes of bladder cancer. Cancer Lett., 2016, 376(1), 155-164.
[http://dx.doi.org/10.1016/j.canlet.2016.03.037] [PMID: 27018306]
[15]
Li, J.; Zhuang, C.; Liu, Y.; Chen, M.; Zhou, Q.; Chen, Z.; He, A.; Zhao, G.; Guo, Y.; Wu, H.; Cai, Z.; Huang, W. shRNA targeting long non-coding RNA CCAT2 controlled by tetracycline-inducible system inhibits progression of bladder cancer cells. Oncotarget, 2016, 7(20), 28989-28997.
[http://dx.doi.org/10.18632/oncotarget.8259] [PMID: 27015551]
[16]
Zhuang, C.; Li, J.; Liu, Y.; Chen, M.; Yuan, J.; Fu, X.; Zhan, Y.; Liu, L.; Lin, J.; Zhou, Q.; Xu, W.; Zhao, G.; Cai, Z.; Huang, W. Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. Oncotarget, 2015, 6(38), 41194-41203.
[http://dx.doi.org/10.18632/oncotarget.5880] [PMID: 26517688]
[17]
Chen, M.; Li, J.; Zhuang, C. Increased lncRNA ABHD11-AS1 represses the malignant phenotypes of bladder cancer. Oncotarget, 2017, 8(17), 28176-28186.
[http://dx.doi.org/10.18632/oncotarget.14945]
[18]
Wei, T.; Zhang, X.; Zhang, Q.; Yang, J.; Chen, Q.; Wang, J.; Li, X.; Chen, J.; Ma, T.; Li, G.; Gao, S.; Lou, J.; Que, R.; Wang, Y.; Dang, X.; Zheng, L.; Liang, T.; Bai, X. Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patients with pancreatic cancer. Cancer Lett., 2019, 452, 237-243.
[http://dx.doi.org/10.1016/j.canlet.2019.03.009] [PMID: 30905814]
[19]
Polireddy, K.; Singh, K.; Pruski, M.; Jones, N.C.; Manisundaram, N.V.; Ponnela, P.; Ouellette, M.; Van Buren, G.; Younes, M.; Bynon, J.S.; Dar, W.A.; Bailey, J.M. Mutant p53R175H promotes cancer initiation in the pancreas by stabilizing HSP70. Cancer Lett., 2019, 453, 122-130.
[http://dx.doi.org/10.1016/j.canlet.2019.03.047] [PMID: 30946870]
[20]
Xu, X.; Zhao, Z.; Guo, S.; Li, J.; Liu, S.; You, Y.; Ni, B.; Wang, H.; Bie, P. Increased semaphorin 3c expression promotes tumor growth and metastasis in pancreatic ductal adenocarcinoma by activating the ERK1/2 signaling pathway. Cancer Lett., 2017, 397, 12-22.
[http://dx.doi.org/10.1016/j.canlet.2017.03.014] [PMID: 28315433]
[21]
Utomo, W.K.; Narayanan, V.; Biermann, K.; van Eijck, C.H.; Bruno, M.J.; Peppelenbosch, M.P.; Braat, H. mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma. Cancer Lett., 2014, 346(2), 309-317.
[http://dx.doi.org/10.1016/j.canlet.2014.01.014] [PMID: 24467966]
[22]
Zhu, Y.; Gu, J.; Li, Y.; Peng, C.; Shi, M.; Wang, X.; Wei, G.; Ge, O.; Wang, D.; Zhang, B.; Wu, J.; Zhong, Y.; Shen, B.; Chen, H. MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes. Cancer Lett., 2018, 412, 59-68.
[http://dx.doi.org/10.1016/j.canlet.2017.09.044] [PMID: 28987387]
[23]
Zheng, S.; Chen, H.; Wang, Y.; Gao, W.; Fu, Z.; Zhou, Q.; Jiang, Y.; Lin, Q.; Tan, L.; Ye, H.; Zhao, X.; Luo, Y.; Li, G.; Ye, L.; Liu, Y.; Li, W.; Li, Z.; Chen, R. Long non-coding RNA LOC389641 promotes progression of pancreatic ductal adenocarcinoma and increases cell invasion by regulating E-cadherin in a TNFRSF10A related manner. Cancer Lett., 2016, 371(2), 354-365.
[http://dx.doi.org/10.1016/j.canlet.2015.12.010] [PMID: 26708505]
[24]
Fu, Y.; Liu, S.; Zeng, S.; Shen, H. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol. Cancer, 2018, 17(1), 62.
[http://dx.doi.org/10.1186/s12943-018-0815-z] [PMID: 29458370]
[25]
Li, H.; Wang, X.; Wen, C.; Huo, Z.; Wang, W.; Zhan, Q.; Cheng, D.; Chen, H.; Deng, X.; Peng, C.; Shen, B. Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer. Mol. Cancer, 2017, 16(1), 169.
[http://dx.doi.org/10.1186/s12943-017-0738-0] [PMID: 29121972]
[26]
Birnbaum, D.J.; Finetti, P.; Birnbaum, D.; Mamessier, E.; Bertucci, F. Validation and comparison of the molecular classifications of pancreatic carcinomas. Mol. Cancer, 2017, 16(1), 168.
[http://dx.doi.org/10.1186/s12943-017-0739-z] [PMID: 29110659]
[27]
Wu, S.G.; Shih, J.Y. 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]
[28]
Chen, H.T.; Liu, H.; Mao, M.J.; Tan, Y.; Mo, X.Q.; Meng, X.J.; Cao, M.T.; Zhong, C.Y.; Liu, Y.; Shan, H.; Jiang, G.M. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol. Cancer, 2019, 18(1), 101.
[http://dx.doi.org/10.1186/s12943-019-1030-2] [PMID: 31126310]
[29]
Li, J.; Zhuang, C.; Liu, Y. Synthetic tetracycline-controllable shRNA targeting long non-coding RNA HOXD-AS1 inhibits the progression of bladder cancer. J. Experim. Clin. Cancer Res.: CR, 2016, 35(1), 99.
[30]
Huang, H.; Zepp, M.; Georges, R.B. The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction. Cancer Lett., 2020, 474, 2-93.
[31]
Wang, K.; Zhan, Y.; Huynh, N. Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1. Cancer Lett., 2020, 472, 8-18.
[32]
Yue, Y.; Qian, W.; Li, J. 2′-Hydroxyflavanone inhibits the progression of pancreatic cancer cells and sensitizes the chemosensitivity of EGFR inhibitors via repressing STAT3 signaling. Cancer Lett., 2020, 471, 135-146.
[33]
Caputo, D. Nanoparticle-enabled blood tests for early detection of pancreatic ductal adenocarcinoma. Cancer Lett., 2020, 470, 191-196.
[34]
Choi, E.A.; Choi, Y.S.; Lee, E.J. A pharmacogenomic analysis using L1000CDS identifies BX-795 as a potential anticancer drug for primary pancreatic ductal adenocarcinoma cells. Cancer Lett., 2019, 465, 82.
[35]
Quan, M.Y.; Guo, Q.; Liu, J.; Yang, R.; Bai, J.; Wang, W.; Cai, Y.; Han, R.; Lv, Y-Q.; Ding, L.; Billadeau, D.D.; Lou, Z.; Bellusci, S.; Li, X.; Zhang, J-S. An FGFR/AKT/SOX2 signaling axis controls pancreatic cancer stemness. Front. Cell Dev. Biol., 2020, 8, 287.
[36]
Pu, N.; Gao, S.; Yin, H. Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway. Cancer Lett., 2019, 460, 42-53.
[37]
Awasthi, N.; Kronenberger, D.; Stefaniak, A. Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer. Cancer Lett., 2019, 459, 41-49.
[38]
Wang, H.; Jia, R.; Zhao, T. HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma. Cancer Lett., 2019, 453, 10-20.
[39]
Wei, T.; Zhang, X.; Zhang, Q. Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patients with pancreatic cancer. Cancer Lett., 2019, 452, 237.
[40]
Vendrely, V.; Amintas, S.; Noel, C. Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death. Cancer Lett., 2019, 451, 1-10.
[41]
Kumar, D.; Sarma, P.; Bhadra, M.P. Impact of The hybrid-polar histone deacetylase inhibitor m-carboxycinnamic acid bis-hydroxamide on human pancreatic adenocarcinoma cells. Anticancer. Agents Med. Chem., 2019, 19(6), 750-759.
[42]
Quilles, J.C., Jr; Bernardi, M.D.L.; Batista, P.H.J.; Silva, S.C.M.; Rocha, C.M.R.; Montanari, C.A.; Leitão, A. Biological activity and physicochemical properties of dipeptidyl nitrile derivatives against pancreatic ductal adenocarcinoma cells. Anticancer. Agents Med. Chem., 2019, 19(1), 112-120.
[http://dx.doi.org/10.2174/1871520618666181029141649] [PMID: 30370859]
[43]
Bartscht, T.; Rosien, B.; Rades, D.; Kaufmann, R.; Biersack, H.; Lehnert, H.; Ungefroren, H. TGF-β signal transduction in pancreatic carcinoma cells is sensitive to inhibition by the Src tyrosine kinase inhibitor AZM475271. Anticancer. Agents Med. Chem., 2017, 17(7), 966-972.
[http://dx.doi.org/10.2174/1871520616666160926110513] [PMID: 27671303]
[44]
Kocdor, M.A.; Cengiz, H.; Ates, H.; Kocdor, H. Inhibition of cancer stem-like phenotype by curcumin and deguelin in CAL-62 anaplastic thyroid cancer cells. Anticancer. Agents Med. Chem., 2019, 19(15), 1887-1898.
[http://dx.doi.org/10.2174/1871520619666191004144025] [PMID: 31584382]
[45]
Hanikoglu, A.; Kucuksayan, E.; Hanikoglu, F.; Ozben, T.; Menounou, G.; Sansone, A.; Chatgilialoglu, C.; Di Bella, G.; Ferreri, C. Effects of somatostatin and vitamin C on the fatty acid profile of breast cancer cell membranes. Anticancer. Agents Med. Chem., 2019, 19(15), 1899-1909.
[http://dx.doi.org/10.2174/1871520619666190930130732] [PMID: 31566138]
[46]
Patel, R.V.; Mistry, B.M.; Syed, R.; Parekh, N.M.; Shin, H.S. Pyrrolo[1,2-a]azepines coupled with benzothiazole and fluorinated aryl thiourea scaffolds as promising antioxidant and anticancer agents. Anticancer. Agents Med. Chem., 2019, 19(15), 1855-1862.
[http://dx.doi.org/10.2174/1871520619666190820151043] [PMID: 31429695]
[47]
Saha, S.; Giri, T.K. Breaking the barrier of cancer through papaya extract and their formulation. Anticancer. Agents Med. Chem., 2019, 19(13), 1577-1587.
[http://dx.doi.org/10.2174/1871520619666190722160955] [PMID: 31418665]
[48]
Zhu, L.; Xi, P.W.; Li, X.X.; Sun, X.; Zhou, W.B.; Xia, T.S.; Shi, L.; Hu, Y.; Ding, Q.; Wei, J.F. Correction to: The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression. J. Exp. Clin. Cancer Res., 2020, 39(1), 21.
[http://dx.doi.org/10.1186/s13046-019-1509-0] [PMID: 31987045]
[49]
Huang, X.Y.; Huang, Z.L.; Huang, J.; Xu, B.; Huang, X.Y.; Xu, Y.H.; Zhou, J.; Tang, Z.Y. Exosomal circRNA-100338 promotes hepatocellular carcinoma metastasis via enhancing invasiveness and angiogenesis. J. Exp. Clin. Cancer Res., 2020, 39(1), 20.
[http://dx.doi.org/10.1186/s13046-020-1529-9] [PMID: 31973767]
[50]
Xia, W.; Liu, Y.; Cheng, T.; Xu, T.; Dong, M.; Hu, X. Down-regulated lncRNA SBF2-AS1 inhibits tumorigenesis and progression of breast cancer by sponging microRNA-143 and repressing RRS1. J. Exp. Clin. Cancer Res., 2020, 39(1), 18.
[http://dx.doi.org/10.1186/s13046-020-1520-5] [PMID: 31952549]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 12
Year: 2020
Published on: 07 September, 2020
Page: [1447 - 1458]
Pages: 12
DOI: 10.2174/1871520620666200508090515
Price: $65

Article Metrics

PDF: 38
HTML: 3
EPUB: 1
PRC: 1



Most Downloaded Article(s)