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Article

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
  • View Affiliations / Copyright

    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
  • Pages: 365-375
    |
    Published online on: April 26, 2016
       https://doi.org/10.3892/or.2016.4770
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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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Copy and paste a formatted citation
Spandidos Publications style
Jiang Z, Huang J, Xie C, Li X, Liu L, He J, Pan H, Huang L, Fan X, Yao X, Yao X, et al: Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations. Oncol Rep 36: 365-375, 2016.
APA
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J. ... Leung, E.L. (2016). Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations. Oncology Reports, 36, 365-375. https://doi.org/10.3892/or.2016.4770
MLA
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J., Pan, H., Huang, L., Fan, X., Yao, X., Xie, Y., Li, N., Liu, L., He, J., Leung, E. L."Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations". Oncology Reports 36.1 (2016): 365-375.
Chicago
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J., Pan, H., Huang, L., Fan, X., Yao, X., Xie, Y., Li, N., Liu, L., He, J., Leung, E. L."Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations". Oncology Reports 36, no. 1 (2016): 365-375. https://doi.org/10.3892/or.2016.4770
Copy and paste a formatted citation
x
Spandidos Publications style
Jiang Z, Huang J, Xie C, Li X, Liu L, He J, Pan H, Huang L, Fan X, Yao X, Yao X, et al: Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations. Oncol Rep 36: 365-375, 2016.
APA
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J. ... Leung, E.L. (2016). Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations. Oncology Reports, 36, 365-375. https://doi.org/10.3892/or.2016.4770
MLA
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J., Pan, H., Huang, L., Fan, X., Yao, X., Xie, Y., Li, N., Liu, L., He, J., Leung, E. L."Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations". Oncology Reports 36.1 (2016): 365-375.
Chicago
Jiang, Z., Huang, J., Xie, C., Li, X., Liu, L., He, J., Pan, H., Huang, L., Fan, X., Yao, X., Xie, Y., Li, N., Liu, L., He, J., Leung, E. L."Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations". Oncology Reports 36, no. 1 (2016): 365-375. https://doi.org/10.3892/or.2016.4770
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