The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer
Hodaka Tayama1, Hideaki Karasawa1, Akihiro Yamamura1
1Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
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.
Insights
Patient-derived organoids (PDOs) show promise for predicting colorectal cancer (CRC) response to ERK inhibitors like SCH772984. Molecular status in PDOs correlates with drug sensitivity, aiding precision medicine for CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The mitogen-activated protein kinase (MAPK) pathway is crucial in colorectal cancer (CRC) progression, often driven by BRAF or KRAS mutations.
- Extracellular signal-regulated kinase (ERK) inhibitors show efficacy, but clinical response doesn't always align with molecular profiles.
Purpose of the Study:
- To investigate the correlation between molecular characteristics and sensitivity to the ERK inhibitor SCH772984 using patient-derived organoids (PDOs) from CRC specimens.
- To assess the utility of PDOs as a model for predicting drug response in colorectal cancer.
Main Methods:
- Drug sensitivity testing of SCH772984 was performed on 14 CRC cell lines and 7 CRC patient-derived organoids (PDOs).
- Molecular profiling via next-generation sequencing (NGS) was conducted on the CRC specimens.
Main Results:
- SCH772984 sensitivity in cell lines correlated with BRAF mutations but not entirely with KRAS status.
- In PDOs, 6/7 cases with BRAF or KRAS mutations were sensitive to SCH772984, while 5/6 wild-type cases were resistant.
- Molecular status in clinical specimens generally reflected sensitivity in PDOs, though not always perfectly.
Conclusions:
- PDOs effectively model drug sensitivity for ERK inhibitors in colorectal cancer.
- PDOs may overcome limitations of gene panels, offering a valuable tool for precision medicine in CRC.
- Molecular profiling combined with PDO drug screening provides a robust approach for personalized CRC treatment strategies.
