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Molecular Cancer Research
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Cancer Genes and Networks

Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids

Shiki Fujino, Norikatsu Miyoshi, Aya Ito, Masayoshi Yasui, Masayuki Ohue, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki and Hidetoshi Eguchi
Shiki Fujino
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
2Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Osaka, Japan.
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Norikatsu Miyoshi
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
2Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Osaka, Japan.
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  • For correspondence: nmiyoshi@gesurg.med.osaka-u.ac.jp
Aya Ito
2Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Osaka, Japan.
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Masayoshi Yasui
3Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.
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Masayuki Ohue
3Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.
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Takayuki Ogino
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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Hidekazu Takahashi
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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Mamoru Uemura
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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Chu Matsuda
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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  • ORCID record for Chu Matsuda
Tsunekazu Mizushima
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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Yuichiro Doki
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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Hidetoshi Eguchi
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
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DOI: 10.1158/1541-7786.MCR-20-0600
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Abstract

Recently developed molecularly targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly targeted therapy in colorectal cancer. We used multiple colorectal cancer cell lines to investigate the growth-inhibitory effect of crenolanib and its effect in combination with other cytotoxic agents. Primary cultures of patient-derived organoids (PDO), a model that reflects the heterogeneity of clinical colorectal cancer, were used to further validate the effects of crenolanib. Unlike cetuximab, crenolanib remarkably suppressed ERK and AKT/mTOR pathways in HT29 cells with BRAF mutation and in HCT116 cells with KRAS mutation with corresponding growth-suppressing effects. Additive or synergistic effects were observed in treatments with combination of crenolanib and other cytotoxic drugs. Moreover, crenolanib suppressed the expression of stem cell markers, such as OCT4, NANOG, and SOX2. These observations were substantiated in seven PDOs with KRAS mutation and two PDOs without KRAS/BRAF mutations, with crenolanib suppressing the growth of all PDOs regardless of their KRAS mutation status. Furthermore, crenolanib abrogated PDGF- and TGFβ-induced increase of OCT4-positive cells in PDOs. Together, these findings suggest that crenolanib may have clinical utility for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.

Implications: These findings indicate that crenolanib can be a useful target agent for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.

Footnotes

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

  • Mol Cancer Res 2021;XX:XX–XX

  • Received July 7, 2020.
  • Revision received November 5, 2020.
  • Accepted February 8, 2021.
  • Published first February 12, 2021.
  • ©2021 American Association for Cancer Research.

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This OnlineFirst version was published on February 26, 2021
doi: 10.1158/1541-7786.MCR-20-0600

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Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids
Shiki Fujino, Norikatsu Miyoshi, Aya Ito, Masayoshi Yasui, Masayuki Ohue, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki and Hidetoshi Eguchi
Mol Cancer Res February 26 2021 DOI: 10.1158/1541-7786.MCR-20-0600

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Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids
Shiki Fujino, Norikatsu Miyoshi, Aya Ito, Masayoshi Yasui, Masayuki Ohue, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki and Hidetoshi Eguchi
Mol Cancer Res February 26 2021 DOI: 10.1158/1541-7786.MCR-20-0600
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Molecular Cancer Research
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