The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling

Summary

Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti-tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, Paz-Ares L (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389(10066):299–311. https://doi.org/10.1016/S0140-6736(16)30958-8

    Article  CAS  Google Scholar 

  2. 2.

    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. https://doi.org/10.3322/caac.21262

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Ray MR, Jablons D, He B (2010) Lung cancer therapeutics that target signaling pathways: an update. Expert Rev Respir Med 4(5):631–645. https://doi.org/10.1586/ers.10.64

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH, Eastern Cooperative Oncology G (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346(2):92–98. https://doi.org/10.1056/NEJMoa011954

    Article  CAS  Google Scholar 

  5. 5.

    J E, Xing J, Gong H, He J, Zhang W (2015) Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9. Tumor Biol 36(2):1091–1097. https://doi.org/10.1007/s13277-014-2667-5

    Article  CAS  Google Scholar 

  6. 6.

    Gadgeel SM, Wozniak A (2013) Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. Clin Lung Cancer 14(4):322–332. https://doi.org/10.1016/j.cllc.2012.12.001

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Rusconi P, Caiola E, Broggini M (2012) RAS/RAF/MEK inhibitors in oncology. Curr Med Chem 19(8):1164–1176

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Forde PM, Ettinger DS (2013) Targeted therapy for non-small-cell lung cancer: past, present and future. Expert Rev Anticancer Ther 13(6):745–758. https://doi.org/10.1586/era.13.47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Heavey S, O'Byrne KJ, Gately K (2014) Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC. Cancer Treat Rev 40(3):445–456. https://doi.org/10.1016/j.ctrv.2013.08.006

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Xu CX, Li Y, Yue P, Owonikoko TK, Ramalingam SS, Khuri FR, Sun SY (2011) The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo. PLoS One 6(6):e20899. https://doi.org/10.1371/journal.pone.0020899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7(7):1851–1863. https://doi.org/10.1158/1535-7163.MCT-08-0017

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, Luengo JI, Newlander KA, Parrish CA, Ridgers LH, Sarpong MA, Schmidt SJ, Van Aller GS, Carson JD, Diamond MA, Elkins PA, Gardiner CM, Garver E, Gilbert SA, Gontarek RR, Jackson JR, Kershner KL, Luo L, Raha K, Sherk CS, Sung CM, Sutton D, Tummino PJ, Wegrzyn RJ, Auger KR, Dhanak D (2010) Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med Chem Lett 1(1):39–43. https://doi.org/10.1021/ml900028r

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Shao T, Wang J, Chen JG, Wang XM, Li H, Li YP, Li Y, Yang GD, Mei QB, Zhang SQ (2014) Discovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agents by bioisostere. Eur J Med Chem 75:96–105. https://doi.org/10.1016/j.ejmech.2014.01.053

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844. https://doi.org/10.1038/nrd2130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A (2007) Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist 12(2):191–200. https://doi.org/10.1634/theoncologist.12-2-191

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Blumenschein G Jr (2008) Sorafenib in lung cancer: clinical developments and future directions. J Thorac Oncol 3(6 Suppl 2):S124–S127. https://doi.org/10.1097/JTO.0b013e318174e085

    Article  PubMed  Google Scholar 

  17. 17.

    Smit EF, Dingemans AM, Thunnissen FB, Hochstenbach MM, van Suylen RJ, Postmus PE (2010) Sorafenib in patients with advanced non-small cell lung cancer that harbor K-ras mutations: a brief report. J Thorac Oncol 5(5):719–720. https://doi.org/10.1097/JTO.0b013e3181d86ebf

    Article  PubMed  Google Scholar 

  18. 18.

    Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhasz E, Aren O, Sun Y, Schmelter T, Ong TJ, Pena C, Smit EF, Mok TS (2015) Monotherapy Administration of Sorafenib in patients with non-small cell lung Cancer (MISSION) trial: a phase III, multicenter, placebo-controlled trial of Sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung Cancer after 2 or 3 previous treatment regimens. J Thorac Oncol 10(12):1745–1753. https://doi.org/10.1097/JTO.0000000000000693

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR Jr, Tsao A, Stewart DJ, Hicks ME, Erasmus J Jr, Gupta S, Alden CM, Liu S, Tang X, Khuri FR, Tran HT, Johnson BE, Heymach JV, Mao L, Fossella F, Kies MS, Papadimitrakopoulou V, Davis SE, Lippman SM, Hong WK (2011) The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 1(1):44–53. https://doi.org/10.1158/2159-8274.CD-10-0010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    O'Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ, Woulfe DS, Brass LF (2000) Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 275(18):13502–13509

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55

    Article  CAS  Google Scholar 

  22. 22.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  Google Scholar 

  23. 23.

    Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118(9):3065–3074. https://doi.org/10.1172/JCI34739

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wan X, Harkavy B, Shen N, Grohar P, Helman LJ (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940. https://doi.org/10.1038/sj.onc.1209990

    Article  CAS  Google Scholar 

  25. 25.

    Sosman JA, Puzanov I, Atkins MB (2007) Opportunities and obstacles to combination targeted therapy in renal cell cancer. Clin Cancer Res 13(2 Pt 2):764s–769s. https://doi.org/10.1158/1078-0432.CCR-06-1975

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257. https://doi.org/10.1038/35025220

    Article  CAS  Google Scholar 

  27. 27.

    Zhan P, Wang J, Lv XJ, Wang Q, Qiu LX, Lin XQ, Yu LK, Song Y (2009) Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol 4(9):1094–1103. https://doi.org/10.1097/JTO.0b013e3181a97e31

    Article  PubMed  Google Scholar 

  28. 28.

    Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL, Llovet JM (2009) Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 51(4):725–733. https://doi.org/10.1016/j.jhep.2009.03.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by a grant from the Shanghai Science and Technology Committee (No.18DZ2290900).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Zhiyong Wang or Qibing Mei.

Ethics declarations

Conflict of interest

Juan Wang declares that she has no conflict of interest. Shumei Ma declares that she has no conflict of interest. Xiuhua Chen declares that she has no conflict of interest. Sanqi Zhang declares that he has no conflict of interest. Zhiyong Wang declares that he has no conflict of interest. Qibing Mei declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

Informed constent was obtained from all individual participants included in this study.

Electronic supplementary material

Supplemental Figure 1
figure7

(PNG 270 kb)

Supplemental Figure 2
figure8

(PNG 175 kb)

Supplemental Figure 3
figure9

(PNG 301 kb)

Supplemental Figure 4
figure10

(PNG 265 kb)

ESM 1

(DOCX 21 kb)

High Resolution (TIF 476 kb)

High Resolution (TIF 300 kb)

High Resolution (TIF 433 kb)

High Resolution (TIF 2242 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Ma, S., Chen, X. et al. The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling. Invest New Drugs 37, 828–836 (2019). https://doi.org/10.1007/s10637-018-0698-2

Download citation

Keywords

  • Lung cancer
  • Sorafenib
  • S1
  • Angiogenesis
  • Phosphorylation