Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Lu,Yingjie; Bian,Dongliang; Zhang,Xuelin; Zhang,Huibiao; Zhu,Zhenghong

doi:10.3892/mmr.2020.11686

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer

Authors:
- Yingjie Lu
- Dongliang Bian
- Xuelin Zhang
- Huibiao Zhang
- Zhenghong Zhu
View Affiliations

Affiliations: Department of Thoracic, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
Published online on: November 12, 2020 https://doi.org/10.3892/mmr.2020.11686
Article Number: 48
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non‑small cell lung cancer (NSCLC) harboring EGFR‑activating mutations; however, acquired resistance limits their long‑term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third‑generation EGFR tyrosine kinase inhibitor, the osimertinib‑resistant NSCLC cell sub‑line HCC827/OR was established in the present study. It was found that the expression levels of Bcl‑2 and Bcl‑xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl‑2 and Bcl‑xL through small interfering RNA‑mediated gene knockdown or using a small molecule specific inhibitor ABT‑263 re‑sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT‑263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT‑263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Siegel RL and Jemal A: Lung cancer statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar : PubMed/NCBI
3	Pao W and Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 10:760–774. 2010. View Article : Google Scholar : PubMed/NCBI
4	Nan X, Xie C, Yu X and Liu J: EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget. 8:75712–75726. 2017. View Article : Google Scholar : PubMed/NCBI
5	Gazdar AF: Activating and resistance mutations of EGFR in non-small-cell lung cancer: Role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 28 (Suppl 1):S24–S31. 2009. View Article : Google Scholar : PubMed/NCBI
6	Lee CC, Shiao HY, Wang WC and Hsieh HP: Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer. Expert Opin Investig Drugs. 23:1333–1348. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M and Riely GJ: Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 19:2240–2247. 2013. View Article : Google Scholar : PubMed/NCBI
8	Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, Ho BC, Chang GC, Shih JY, Yu SL, et al: Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 30:433–440. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, et al: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4:1046–1061. 2014. View Article : Google Scholar : PubMed/NCBI
10	Soejima K, Yasuda H and Hirano T: Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer. Expert Rev Clin Phar. 10:31–38. 2017. View Article : Google Scholar
11	Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, et al: Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 21:560–562. 2015. View Article : Google Scholar : PubMed/NCBI
12	Ricordel C, Friboulet L, Facchinetti F and Soria JC: Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer. Ann Oncol. 29 (Suppl 1):i28–i37. 2018. View Article : Google Scholar : PubMed/NCBI
13	Shi P, Oh Y-T, Deng L, Zhang G, Qian G, Zhang S, Ren H, Wu G, Legendre B Jr, Anderson E, et al: Overcoming acquired resistance to AZD9291, a third-generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation. Clin Cancer Res. 23:6567–6579. 2017. View Article : Google Scholar : PubMed/NCBI
14	Zou M, Xia S, Zhuang L, Han N, Chu Q, Chao T, Peng P, Chen Y, Gui Q and Yu S: Knockdown of the Bcl-2 gene increases sensitivity to EGFR tyrosine kinase inhibitors in the H1975 lung cancer cell line harboring T790M mutation. Int J Oncol. 42:2094–2102. 2013. View Article : Google Scholar : PubMed/NCBI
15	Nakajima W, Sharma K, Hicks MA, Le N, Brown R, Krystal GW and Harada H: Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer. Cancer Biol Ther. 17:27–35. 2016. View Article : Google Scholar : PubMed/NCBI
16	Emi M, Kim R, Tanabe K, Uchida Y and Toge T: Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 7:R940–R952. 2005. View Article : Google Scholar : PubMed/NCBI
17	Beale PJ, Rogers P, Boxall F, Sharp SY and Kelland LR: BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma. Br J Cancer. 82:436–440. 2000. View Article : Google Scholar : PubMed/NCBI
18	Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K and Takei Y: Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer. 125:2978–2990. 2009. View Article : Google Scholar : PubMed/NCBI
19	Quadros MR, Connelly S, Kari C, Abrams MT, Wickstrom E and Rodeck U: EGFR-dependent downregulation of Bim in epithelial cells requires MAPK and PKC-delta activities. Cancer Biol Ther. 5:498–504. 2006. View Article : Google Scholar : PubMed/NCBI
20	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
21	Sukrithan V, Deng L, Barbaro A and Cheng H: Emerging drugs for EGFR-mutated non-small cell lung cancer. Expert Opin Emerg Drugs. 24:5–16. 2019. View Article : Google Scholar : PubMed/NCBI
22	Wu SG and Shih JY: Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 17:382018. View Article : Google Scholar : PubMed/NCBI
23	Santarpia M, Liguori A, Karachaliou N, Gonzalez-Cao M, Daffinà MG, D'Aveni A, Marabello G, Altavilla G and Rosell R: Osimertinib in the treatment of non-small-cell lung cancer: Design, development and place in therapy. Lung Cancer (Auckl). 8:109–125. 2017.PubMed/NCBI
24	Bollinger MK, Agnew AS and Mascara GP: Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation. J Oncol Pharm Pract. 24:379–388. 2018. View Article : Google Scholar : PubMed/NCBI
25	Lazzari C, Gregorc V, Karachaliou N, Rosell R and Santarpia M: Mechanisms of resistance to osimertinib. J Thorac Dis. 12:2851–2858. 2020. View Article : Google Scholar : PubMed/NCBI
26	Kitada S, Pedersen IM, Schimmer AD and Reed JC: Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene. 21:3459–3474. 2002. View Article : Google Scholar : PubMed/NCBI
27	Yamaguchi R, Lartigue L and Perkins G: Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy. Pharmacol Ther. 195:13–20. 2019. View Article : Google Scholar : PubMed/NCBI
28	Faber AC, Farago AF, Costa C, Dastur A, Gomez-Caraballo M, Robbins R, Wagner BL, Rideout WM III, Jakubik CT, Ham J, et al: Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. Proc Natl Acad Sci USA. 112:E1288–E1296. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sarosiek KA, Ni Chonghaile T and Letai A: Mitochondria: Gatekeepers of response to chemotherapy. Trends Cell Biol. 23:612–619. 2013. View Article : Google Scholar : PubMed/NCBI
30	Lu M, Liu B, Xiong H, Wu F, Hu C and Liu P: Trans-3,5,4-trimethoxystilbene reduced gefitinib resistance in NSCLCs via suppressing MAPK/Akt/Bcl-2 pathway by upregulation of miR-345 and miR-498. J Cell Mol Med. 23:2431–2441. 2019. View Article : Google Scholar : PubMed/NCBI
31	Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, et al: ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68:3421–3428. 2008. View Article : Google Scholar : PubMed/NCBI
32	Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G and Vandenabeele P: Toxic proteins released from mitochondria in cell death. Oncogene. 23:2861–2874. 2004. View Article : Google Scholar : PubMed/NCBI
33	Sarosiek KA, Chi X, Bachman JA, Sims JJ, Montero J, Patel L, Flanagan A, Andrews DW, Sorger P and Letai A: BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell. 51:751–765. 2013. View Article : Google Scholar : PubMed/NCBI
34	Shukla S, Saxena S, Singh BK and Kakkar P: BH3-only protein BIM: An emerging target in chemotherapy. Eur J Cell Biol. 96:728–738. 2017. View Article : Google Scholar : PubMed/NCBI