The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer

Hodaka Tayama, Hideaki Karasawa, Akihiro Yamamura, Yasunobu Okamura, Fumiki Katsuoka, Hideyuki Suzuki, Taiki Kajiwara, Minoru Kobayashi, Yuuri Hatsuzawa, Masahiro Shiihara, Li Bin, Md Yeashin Gazi, Mizuki Sato, Kazuki Kumada, Shigehiro Ito, Muneaki Shimada, Toru Furukawa, Takashi Kamei, Shinobu Ohnuma, Michiaki Unno

Research output: Contribution to journalArticlepeer-review

Abstract

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

Original languageEnglish
Pages (from-to)59-65
Number of pages7
JournalBiochemical and biophysical research communications
Volume560
DOIs
Publication statusPublished - 2021 Jun 30

Keywords

  • ERK inhibitor
  • MAPK
  • NGS
  • PDO

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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