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Tumor microenvironment confers mTOR inhibitor resistance in invasive intestinal adenocarcinoma

Oncogene volume 36, pages 6480–6489 (2017)Cite this article

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Abstract

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is frequently activated in cancers and can be counteracted with the clinical mTORC1 inhibitors everolimus and temsirolimus. Although mTORC1 and dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. Using the cis-Apc/Smad4 mouse model of locally invasive intestinal adenocarcinoma, we show that administration of everolimus or the dual mTORC1/2 inhibitor AZD8055 significantly reduces the growth of intestinal tumors. In contrast, although everolimus treatment at earlier phase of tumor progression delayed invasion of the tumors, both inhibitors exhibited little effect on blocking invasion of the tumors when administered later in their progression. Biochemical and immunohistochemical analyses revealed that treatment of cis-Apc/Smad4 mice with everolimus or AZD8055 induced marked increases in epidermal growth factor receptor (EGFR) and MEK/ERK signaling in tumor epithelial and stromal cells, respectively. Notably, co-administration of AZD8055 and the EGFR inhibitor erlotinib or the MEK inhibitor trametinib was sufficient to suppress tumor invasion in cis-Apc/Smad4 mice. These data indicate that mTOR inhibitor resistance in invasive intestinal tumors involves feedback signaling from both cancer epithelial and stromal cells, highlighting the role of tumor microenvironment in drug resistance, and support that simultaneous inhibition of mTOR and EGFR or MEK may be more effective in treating colon cancer.

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Acknowledgements

The authors thank PM McSheehy for everolimus; M Oshima, T Kitamura, M Sonoshita, S Arimura, F Kakizaki, A Deguchi, K Sakuma and K Aoki for discussions; and R Mitsuya, M Tsuda, A Kojima, K Kobori and Y Goto for technical assistance. This work was supported by JSPS KAKENHI Grant Number 24790382 (to TF), Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare (to MA), The Yasuda Medical Foundation, Suzuken Memorial Foundation, Nagono Medical Foundation, The Shimabara Science Promotion Foundation (to TF), Takeda Science Foundation (to TF and MA), and Princess Takamatsu Cancer Research Fund (to MA).

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Authors and Affiliations

  1. Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan

    T Fujishita, Y Kojima, R Kajino-Sakamoto & M Aoki

  2. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo-ku, Kyoto, Japan

    T Fujishita & M M Taketo

  3. Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Aoki

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  1. T Fujishita
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Correspondence to M Aoki.

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Fujishita, T., Kojima, Y., Kajino-Sakamoto, R. et al. Tumor microenvironment confers mTOR inhibitor resistance in invasive intestinal adenocarcinoma. Oncogene 36, 6480–6489 (2017). https://doi.org/10.1038/onc.2017.242

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