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Published on: September 30, 2016
Cell line models for drug discovery in PIK3CA-mutated colorectal cancers
1Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Sainte Marie, ON, P6B 0A8, Canada. ivoutsadakis@yahoo.com.
Abstract:
Colorectal cancer remains a major cause of cancer-related morbidity and mortality. Metastatic disease is still incurable in most cases. New therapies based on a better understanding of the pathogenesis are needed to improve outcomes. Mutations in the catalytic sub-unit of kinase PI3K encoded by gene PIK3CA are common in colorectal cancer cell lines and patient samples. The characteristics of colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE), with and without PIK3CA mutations, were evaluated and compared. A panel of colorectal cancer cell lines with and without PIK3CA mutations were compared for their sensitivity to PIK3 inhibitors. Concomitant molecular abnormalities of sensitive versus resistant cell lines were identified. Colorectal cancer cell lines with PIK3CA mutations are commonly diploid and have microsatellite instability (MSI) and a high tumor mutation burden (TMB), compared with cell lines without PIK3CA mutations. Cell lines with PIK3CA mutations tend to have higher sensitivity to some but not all PI3K inhibitors tested and display variability in sensitivity. Both cell lines with MSI and microsatellite stable (MSS) are among the most sensitive to PI3K inhibitors. Multiple concomitant mutations in the PI3K/AKT and KRAS/BRAF/MEK/ERK pathways are often observed in sensitive cell lines. In concordance with patient samples, colorectal cancer cell lines with PIK3CA mutations display more commonly MSI and tend to be more sensitive to PI3K inhibitors. Variability in sensitivity of PIK3CA-mutated cell lines suggests that additional molecular abnormalities contribute to sensitivity.
Insights
Colorectal cancer cell lines with PIK3CA mutations often exhibit microsatellite instability and higher sensitivity to PI3K inhibitors. However, sensitivity varies, indicating other molecular factors influence treatment response in colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer (CRC) is a significant cause of cancer mortality, with metastatic disease often incurable.
- Improved therapies are needed, driven by a deeper understanding of CRC pathogenesis.
- Mutations in PIK3CA, encoding the PI3K catalytic subunit, are frequent in CRC.
Purpose of the Study:
- To characterize and compare colorectal cancer cell lines with and without PIK3CA mutations.
- To assess the sensitivity of these cell lines to PI3K inhibitors.
- To identify molecular abnormalities associated with PI3K inhibitor sensitivity or resistance.
Main Methods:
- Evaluation and comparison of colorectal cancer cell line characteristics from the Cancer Cell Line Encyclopedia (CCLE).
- Assessment of sensitivity to PI3K inhibitors across a panel of cell lines.
- Identification of concomitant molecular alterations in sensitive versus resistant cell lines.
Main Results:
- PIK3CA-mutated CRC cell lines are often diploid, exhibit microsatellite instability (MSI), and have high tumor mutation burden (TMB).
- These cell lines show variable sensitivity to PI3K inhibitors; both MSI and microsatellite stable (MSS) cell lines can be highly sensitive.
- Sensitive cell lines frequently possess co-occurring mutations in PI3K/AKT and RAS/MAPK pathways.
Conclusions:
- Colorectal cancer cell lines with PIK3CA mutations frequently display MSI and tend towards increased sensitivity to PI3K inhibitors, mirroring patient sample data.
- Variability in PIK3CA-mutated cell line sensitivity suggests that additional molecular abnormalities play a crucial role in determining treatment response.
