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Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

Oncogene volume 32, pages 4427–4435 (2013)Cite this article

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Abstract

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

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Acknowledgements

We thank Dr John D Minna (University of Texas Southwestern Medical Center) and Dr Isaiah J Fidler (MD Anderson Cancer Center, Houston, TX, USA) for kindly provided by H1975 and PC14PE6, respectively. We thank Mrs Takayuki Nakagawa and Kenji Kita (Cancer Research Institute, Kanazawa University) for technical assistance and fruitful discussion. This work was supported in part by the Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare (M Noguchi, 16-1) and was supported by Grants-in-Aid for Cancer Research (T Yamada, 23790902 and S Yano, 21390256) and Scientific Research on Innovative Areas ‘Integrative Research on Cancer Microenvironment Network’ (S Yano, 22112010) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    T Yamada, S Takeuchi, W Wang, Q Li & S Yano

  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    N Fujita & A Nakamura

  3. Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan

    M Oda

  4. Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

    T Mitsudomi

  5. Department of Pathology, Aichi Cancer Center Hospital, Nagoya, Japan

    Y Yatabe

  6. Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Y Sekido

  7. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    J Yoshida

  8. Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

    M Higashiyama

  9. Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan

    M Noguchi

  10. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    H Uehara

  11. Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Y Nishioka & S Sone

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Correspondence to T Yamada.

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Competing interests

Seiji Yano received honoraria from Chugai Pharmaceutical Co., Ltd. and AstraZeneca. Seiji Yano received research funding from Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd. and Eisai Co., Ltd.

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Yamada, T., Takeuchi, S., Fujita, N. et al. Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations. Oncogene 32, 4427–4435 (2013). https://doi.org/10.1038/onc.2012.446

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