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BYL719, a selective inhibitor of phosphoinositide 3-Kinase α, enhances the effect of selumetinib (AZD6244, ARRY-142886) in KRAS-mutant non-small cell lung cancer

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Summary

Purpose KRAS is frequently mutated in non-small cell lung cancers (NSCLC), resulting in activation of the MEK/ERK pathway. Because there are currently no drugs that target oncogenic KRAS, MEK inhibitors have been tested clinically as a possible treatment option for patients with NSCLC. However, KRAS-mutant cancers exhibit resistance to MEK inhibitors. Therefore, a combinational strategy is necessary for effective therapy. To address this, we investigated the therapeutic effects of combining selumetinib, a MEK1/2 inhibitor, with BYL719, a PI3Kα inhibitor. Methods We evaluated the effects of selumetinib and BYL719 in vitro and in vivo in NSCLC cell lines. Results The combination of BYL719 and selumetinib resulted in synergistic cytotoxic activity compared with the single agents alone in KRAS-mutant NSCLC cells. At the molecular level, we found that AKT activation strongly influenced the sensitivity of KRAS-mutant NSCLC cells to selumetinib. Selumetinib upregulated phospho-AKT and phosphorylated BAD at ser136, which is responsible for intrinsic drug resistance in KRAS-mutant NSCLC cells. In contrast, inhibition of the PI3K/AKT pathway by BYL719 hindered selumetinib-induced BAD phosphorylation and increased the antitumor efficacy of selumetinib. Furthermore, selumetinib and BYL719 combination therapy showed synergy in the suppression of A549 xenograft tumor growth. On analysis of the pharmacodynamics, selumetinib and BYL719 together resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue. Conclusion Taken together, these data suggest that combination treatment with selumetinib and BYL719 is a promising therapeutic approach to overcoming resistance to MEK inhibitors.

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Acknowledgments

This study was supported in part by a grant from the Samsung Biomedical Research Institute (GE1-B3-081-1). The authors thank AstraZeneca Pharmaceutics for selumetinib.

Ethical standards

All experiments were performed in accordance with the regulation of the Institutional Animal Care and Use Committee (IACUC) at the Samsung Biomedical Research Institute (SBRI) and with the applicable laws and regulations of Korea.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Samsung Biomedical Research Institute, Seoul, South Korea

    Bo Mi Ku, Eun Hye Jho & Yeon-Hee Bae

  2. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Jong-Mu Sun, Jin Seok Ahn, Keunchil Park & Myung-Ju Ahn

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  1. Bo Mi Ku
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Ku, B.M., Jho, E.H., Bae, YH. et al. BYL719, a selective inhibitor of phosphoinositide 3-Kinase α, enhances the effect of selumetinib (AZD6244, ARRY-142886) in KRAS-mutant non-small cell lung cancer. Invest New Drugs 33, 12–21 (2015). https://doi.org/10.1007/s10637-014-0163-9

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