Ranking small molecules by how much they preferentially inhibit the growth of cancer cell lines with either BRAF or KRAS oncogene mutations

We were interested in the question of whether it might be possible to use knowledge of cancer-related mutations in the cell lines of the NCI60 screening data set to identify small molecules that preferentially inhibit the growth of cell lines containing either BRAF or KRAS oncogene mutations. Our hypothesis was that this cell line mutation knowledge could help to identify small molecules that were more likely to preferentially inhibit growth of cell lines with a particular mutation. It seems that any such molecules might be further investigated to try to better understand the molecular mechanisms of growth inhibition.

We defined a quantity, \(\text{Diff}_{\text{mut}}\), that estimates how much more a given small molecule inhibits cell lines with a mutation of interest than cell lines without that mutation. We ranked the small molecules in descending order of \(\text{Diff}_{\text{mut}}\) and then tried to explain whether the ranking of the highest ranked molecules made sense in terms of independent facts about these molecules.

This method showed the BRAF inhibitor vemurafenib to be highly ranked in the BRAF ranking. The cytidine analog cytarabine was found to be highly ranked in the KRAS ranking. Other cytidine analogs were also found to be highly ranked with respect to KRAS.