New predictive drug response biomarkers for kinase inhibitors approved for clinical use

Introduction

Kinase inhibitors are one of the most important classes of precision medicines. All are used clinically in a specific patient population that is defined by the presence of a drug response biomarker. To refine the application of kinase inhibitors, there is a need of new drug response biomarkers.

Material and Method

One of the best ways to identify new drug response biomarkers is by in vitro profiling in cancer cell line panels. Oncolines is a panel of 102 genetically characterized cell lines from distinct tumour origins. Earlier work [1] has shown that the Oncolines worflow generates highly reproducible data, which is necessary for biomarker discovery. In this study, we profiled all kinase inhibitors that have been approved since November 2013, seventeen in total, in the Oncolines™ panel. This includes the ALK inhibitors ceritinib, brigatinib, and alectinib, the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the BTK inhibitors ibrutinib and acalabrutinib, and nine other novel marketed inhibitors. The cell lines were screened in parallel in proliferation assays based on ATP-lite read-out, with 9 point duplicate dilution series of the compounds. Drug response was quantified by calculation of IC₅₀, and was associated with the mutation status of hundred cancer genes using the statistical software R. The genomic data were retrieved from the COSMIC database and filtered for relevance in primary patient tumour samples. Drug response was also correlated with the basal gene expression levels of 400 clinically actionable genes, retrieved from the Cancer Cell Line Encyclopedia (CCLE).

Results and discussion

Profiling of CDK4/6 inhibitors confirmed previously reported biomarkers, such as low levels of CDKN2A and wild-type RB1. It also suggested new ones, such as TP53 mutation and CCNE1 overexpression. ALK-targeting drugs strongly inhibited cell lines with high expression levels of ALK and also of JAK3. The dual ALK/JAK3 inhibitory profile of brigatinib might explain its efficient targeting of ALK-driven cells, despite its moderate biochemical selectivity.

Conclusion

The profiling of seventeen newly approved kinase inhibitors in the Oncolines panel revealed all clinically-used drug response biomarkers. Clinically used biomarkers, such as ALK or mutant BRAF(V600E), exhibit a high potency difference between marker-positive and marker-negative cell lines, suggesting that there is a certain minimal window needed for biomarkers to be useful. For several kinase inhibitor drugs, the combination multiple drug response biomarkers might improve their clinical success.

[1] Uitdehaag et al. (2016) Molecular Cancer Therapeutics 15, 3091-3109