Cell line models for drug discovery in PIK3CA-mutated colorectal cancers

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.

Automated summary

Colorectal cancer is a major contributor to cancer-related morbidity and mortality, and the majority of metastatic cases remain incurable. New therapies based on a better understanding of the disease's pathogenesis are needed. Mutations in the PIK3CA gene, which encodes the catalytic sub-unit of kinase PI3K, are commonly found in colorectal cancer cell lines and patient samples. Colorectal cancer cell lines with PIK3CA mutations tend to have specific characteristics, such as being diploid, having microsatellite instability, and a high tumor mutation burden. These mutated cell lines demonstrate variable sensitivity to PI3K inhibitors, and often have multiple concomitant mutations in the PI3K/AKT and KRAS/BRAF/MEK/ERK pathways, similar to what is observed in patient samples. The presence of PIK3CA mutations in colorectal cancer cell lines is associated with microsatellite instability and increased sensitivity to PI3K inhibitors.