Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations

Jiang,Ze-Bo; Huang,Jun; Xie,Chun; Li,Xia; Liu,Liping; He,Jiaxi; Pan,Hui; Huang,Liyan; Fan,Xing-Xing; Yao,Xiao-Jun; Xie,Ying; Li,Na; Liu,Liang; He,Jian-Xing; Leung,Elaine  Lai-Han

doi:10.3892/or.2016.4770

Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations

Authors:
- Ze-Bo Jiang
- Jun Huang
- Chun Xie
- Xia Li
- Liping Liu
- Jiaxi He
- Hui Pan
- Liyan Huang
- Xing-Xing Fan
- Xiao-Jun Yao
- Ying Xie
- Na Li
- Liang Liu
- Jian-Xing He
- Elaine Lai-Han Leung
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Affiliations: State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR, P.R. China, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Department of Thoracic Surgery of the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, P.R. China
Published online on: April 26, 2016 https://doi.org/10.3892/or.2016.4770
Pages: 365-375

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Abstract

EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC. The present study aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutations. In addition, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment. Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the same oncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines. Overall, our findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required.

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1	Zardavas D, Fumagalli D and Loi S: Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition: A breakthrough in the management of luminal (ER⁺/HER2⁻) breast cancers? Curr Opin Oncol. 24:623–634. 2012. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	She J, Yang P, Hong Q and Bai C: Lung cancer in China: Challenges and interventions. Chest. 143:1117–1126. 2013. View Article : Google Scholar : PubMed/NCBI
4	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
5	Domvri K, Darwiche K, Zarogoulidis P and Zarogoulidis K: Following the crumbs: From tissue samples, to pharmacogenomics, to NSCLC therapy. Transl Lung Cancer Res. 2:256–258. 2013.PubMed/NCBI
6	Ma BB, Hui EP and Mok TS: Population-based differences in treatment outcome following anticancer drug therapies. Lancet Oncol. 11:75–84. 2010. View Article : Google Scholar : PubMed/NCBI
7	Fumarola C, Bonelli MA, Petronini PG and Alfieri RR: Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 90:197–207. 2014. View Article : Google Scholar : PubMed/NCBI
8	Vansteenkiste JF, Canon JL, Braud FD, Grossi F, De Pas T, Gray JE, Su WC, Felip E, Yoshioka H, Gridelli C, et al: Safety and efficacy of Buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: Results from the Phase II BASALT-1 Study. J Thorac Oncol. 10:1319–1327. 2015. View Article : Google Scholar : PubMed/NCBI
9	Mantripragada K and Khurshid H: Targeting genomic alterations in squamous cell lung cancer. Front Oncol. 3:1952013. View Article : Google Scholar : PubMed/NCBI
10	Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, et al: Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 11:317–328. 2012. View Article : Google Scholar
11	Gupta P, Das PK and Ukil A: Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by Toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Agents Chemother. 59:2531–2539. 2015. View Article : Google Scholar : PubMed/NCBI
12	Heidegger I, Pircher A, Klocker H and Massoner P: Targeting the insulin-like growth factor network in cancer therapy. Cancer Biol Ther. 11:701–707. 2011. View Article : Google Scholar : PubMed/NCBI
13	Vogelstein B and Kinzler KW: Cancer genes and the pathways they control. Nat Med. 10:789–799. 2004. View Article : Google Scholar : PubMed/NCBI
14	Yu JA, Li H, Meng X, Fullerton DA, Nemenoff RA, Mitchell JD and Weyant MJ: Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells. J Thorac Cardiovasc Surg. 144:1479–1485. 2012. View Article : Google Scholar : PubMed/NCBI
15	Simonetti S, Molina MA, Queralt C, de Aguirre I, Mayo C, Bertran-Alamillo J, Sanchez JJ, Gonzalez-Larriba JL, Jimenez U, Isla D, et al: Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer. J Transl Med. 8:1352010. View Article : Google Scholar : PubMed/NCBI
16	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
17	Ware KE, Hinz TK, Kleczko E, Singleton KR, Marek LA, Helfrich BA, Cummings CT, Graham DK, Astling D, Tan AC, et al: A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis. 2:e392013. View Article : Google Scholar : PubMed/NCBI
18	Ren H, Chen M, Yue P, Tao H, Owonikoko TK, Ramalingam SS, Khuri FR and Sun SY: The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo. Cancer Lett. 325:139–146. 2012. View Article : Google Scholar : PubMed/NCBI
19	Zhang Z, Stiegler AL, Boggon TJ, Kobayashi S and Halmos B: EGFR-mutated lung cancer: A paradigm of molecular oncology. Oncotarget. 1:497–514. 2010. View Article : Google Scholar : PubMed/NCBI
20	Roper J, Sinnamon MJ, Coffee EM, Belmont P, Keung L, Georgeon-Richard L, Wang WV, Faber AC, Yun J, Yilmaz ÖH, et al: Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett. 347:204–211. 2014. View Article : Google Scholar : PubMed/NCBI
21	Benjamin D, Colombi M, Moroni C and Hall MN: Rapamycin passes the torch: A new generation of mTOR inhibitors. Nat Rev Drug Discov. 10:868–880. 2011. View Article : Google Scholar : PubMed/NCBI
22	Slomovitz BM and Coleman RL: The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 18:5856–5864. 2012. View Article : Google Scholar : PubMed/NCBI
23	Lonetti A, Antunes IL, Chiarini F, Orsini E, Buontempo F, Ricci F, Tazzari PL, Pagliaro P, Melchionda F, Pession A, et al: Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia. 28:1196–1206. 2014. View Article : Google Scholar
24	Bonelli MA, Cavazzoni A, Saccani F, Alfieri RR, Quaini F, La Monica S, Galetti M, Cretella D, Caffarra C, Madeddu D, et al: Inhibition of PI3K pathway reduces invasiveness and epithelial-to-mesenchymal transition in squamous lung cancer cell lines harboring PIK3CA gene alterations. Mol Cancer Ther. 14:1916–1927. 2015. View Article : Google Scholar : PubMed/NCBI
25	Diamandis M, White NM and Yousef GM: Personalized medicine: Marking a new epoch in cancer patient management. Mol Cancer Res. 8:1175–1187. 2010. View Article : Google Scholar : PubMed/NCBI
26	Antonicelli A, Cafarotti S, Indini A, Galli A, Russo A, Cesario A, Lococo FM, Russo P, Mainini AF, Bonifati LG, et al: EGFR-targeted therapy for non-small cell lung cancer: Focus on EGFR oncogenic mutation. Int J Med Sci. 10:320–330. 2013. View Article : Google Scholar : PubMed/NCBI
27	Stephen AG, Esposito D, Bagni RK and McCormick F: Dragging ras back in the ring. Cancer Cell. 25:272–281. 2014. View Article : Google Scholar : PubMed/NCBI