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Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET

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Abstract

Purpose

This study aimed to determine the correlation between DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) status and the response to streptozocin in advanced well-differentiated pancreatic neuroendocrine tumors (WD panNETs).

Methods

To test the hypothesis that MGMT deficiency was required for an alkylating drug response, we retrospectively reviewed the response of 13 patients with WD panNETs to alkylating agents in relation to MGMT status. We also studied MGMT expression in streptozocin resistance using panNET cell lines.

Results

The cohort included 54% of patients with and 46% without MGMT expression. Among these, 83.3% (5/6) of MGMT-negative cases showed a partial response to streptozocin. In contrast, only 14.2% (1/7) of MGMT-positive cases showed a partial response (P = 0.013). Induced expression of MGMT in BON1 cells (a panNET cell line with undetectable endogenous MGMT) produced streptozocin resistance. Knockdown of MGMT in QGP1 cells, which express MGMT endogenously, did not alter the response to streptozocin.

Conclusions

We observed a relationship between MGMT status and streptozocin response in both patients and cell culture. Despite limited cases examined, high concordance of negative expression of MGMT and response to streptozocin treatment suggest that MGMT expression can be a potential biomarker for this treatment.

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Acknowledgements

The authors extend our sincere appreciation to Dr. Hironori Koga (Kurume University, Kurume, Japan).

Funding

This study was funded by the Aichi Cancer Research Foundation, Japan (K.S.).

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Authors and Affiliations

  1. Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan

    Susumu Hijioka, Nobumasa Mizuno, Takamichi Kuwahara, Nozomi Okuno & Kazuo Hara

  2. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Susumu Hijioka

  3. Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Keiichiro Sakuma & Masahiro Aoki

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

    Masahiro Aoki

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

    Yasushi Yatabe

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  1. Susumu Hijioka
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  2. Keiichiro Sakuma
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  4. Nobumasa Mizuno
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Corresponding author

Correspondence to Susumu Hijioka.

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Conflict of interest

Susumu Hijioka has received speaker honoraria from Novelphama, Novartis, and Teijin Pharma. Nobumasa Mizuno has received research funding from AstraZeneca, Zeria Pharmaceutical, Taiho Pharmaceutical, Merck Serono, Eisai, NanoCarrier, MSD, Dainippon Sumitomo Pharma, and Novartis. Keiichiro Sakuma, Masahiro Aoki, Takamichi Kuwahara, Nozomi Okuno, Kazuo Hara, and Yasushi Yatabe have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Supplementary material 1 (DOCX 22 KB)

Online Resource 1. OS for pancreatic neuroendocrine tumor patients treated with streptozocin therapy

. The solid line is MGMT- negative (deficient) as determined by IHC, and the dotted line is MGMT- positive (intact) as determined by IHC. The median OS of the MGMT negative and MGMT positive groups was 827 days (range,163-1296), and 447 days (range, 81–1218 days), respectively (P = 0.339). (TIF 66 KB)

Online Resource 2

. MTT assay of MGMT-knockdown QGP1 cells treated with streptozocin. MTT activity was assayed in MGMT-knockdown QGP1 subclones treated with streptozocin. P = 0.022 (*) compared with Luc shRNA-transduced QGP1 cells treated with the same concentration of streptozocin. (TIF 167 KB)

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Hijioka, S., Sakuma, K., Aoki, M. et al. Clinical and in vitro studies of the correlation between MGMT and the effect of streptozocin in pancreatic NET. Cancer Chemother Pharmacol 83, 43–52 (2019). https://doi.org/10.1007/s00280-018-3700-y

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