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Molecular Cancer Research
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Signal Transduction and Functional Imaging

SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells

Hideki Terai, Junko Hamamoto, Katsura Emoto, Takeshi Masuda, Tadashi Manabe, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima and Koichi Fukunaga
Hideki Terai
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
2Division of Bioregulatory Medicine, Department of Pharmacology, Kitasato University, Tokyo, Japan.
3Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.
4Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan.
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  • ORCID record for Hideki Terai
  • For correspondence: hidekit926@gmail.com
Junko Hamamoto
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
2Division of Bioregulatory Medicine, Department of Pharmacology, Kitasato University, Tokyo, Japan.
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Katsura Emoto
5Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan.
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Takeshi Masuda
6Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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Tadashi Manabe
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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Satoshi Kuronuma
7Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
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Keigo Kobayashi
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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Keita Masuzawa
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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Shinnosuke Ikemura
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
8Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
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Sohei Nakayama
3Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.
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Ichiro Kawada
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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Yusuke Suzuki
3Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.
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Osamu Takeuchi
7Biomedical Laboratory, Department of Research, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
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Yukio Suzuki
2Division of Bioregulatory Medicine, Department of Pharmacology, Kitasato University, Tokyo, Japan.
3Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.
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Sumio Ohtsuki
6Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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Hiroyuki Yasuda
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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Kenzo Soejima
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
4Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan.
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Koichi Fukunaga
1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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DOI: 10.1158/1541-7786.MCR-20-0664 Published February 2021
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Abstract

EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); however, treatment with EGFR–TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR–TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR–TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR–TKIs and that SHOC2 affects the sensitivity to EGFR–TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations.

Implications: This study showed that SHOC2 works as a modulator of sensitivity to EGFR–TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR–TKIs.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:317–28

  • Received July 30, 2020.
  • Revision received September 16, 2020.
  • Accepted October 19, 2020.
  • Published first October 26, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (2)
February 2021
Volume 19, Issue 2
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SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells
Hideki Terai, Junko Hamamoto, Katsura Emoto, Takeshi Masuda, Tadashi Manabe, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima and Koichi Fukunaga
Mol Cancer Res February 1 2021 (19) (2) 317-328; DOI: 10.1158/1541-7786.MCR-20-0664

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SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells
Hideki Terai, Junko Hamamoto, Katsura Emoto, Takeshi Masuda, Tadashi Manabe, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima and Koichi Fukunaga
Mol Cancer Res February 1 2021 (19) (2) 317-328; DOI: 10.1158/1541-7786.MCR-20-0664
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