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

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.

Keywords: CCLE; Drug development; GDSC; PI3K; Targeted therapies.