Combined kinome inhibition states are predictive of cancer cell line sensitivity to kinase inhibitor combination therapies.

ABSTRACT

Protein kinases are a primary focus in targeted therapy development for cancer, owing to their role as regulators in nearly all areas of cell life. Kinase inhibitors are one of the fastest growing drug classes in oncology, but resistance acquisition to kinase-targeting monotherapies is inevitable due to the dynamic and interconnected nature of the kinome in response to perturbation. Recent strategies targeting the kinome with combination therapies have shown promise, such as the approval of Trametinib and Dabrafenib in advanced melanoma, but similar empirical combination design for less characterized pathways remains a challenge. Computational combination screening is an attractive alternative, allowing in-silico screening prior to in-vitro or in-vivo testing of drastically fewer leads, increasing efficiency and effectiveness of drug development pipelines. In this work, we generate combined kinome inhibition states of 40,000 kinase inhibitor combinations from kinobeads-based kinome profiling across 64 doses. We then integrated these with baseline transcriptomics from CCLE to build robust machine learning models to predict cell line sensitivity from NCI-ALMANAC across nine cancer types, with model accuracy R2 ~ 0.75-0.9 after feature selection using elastic-net regression. We further validated the model's ability to extend to real-world examples by using the best-performing breast cancer model to generate predictions for kinase inhibitor combination sensitivity and synergy in a PDX-derived TNBC cell line and saw reasonable global accuracy in our experimental validation (R2 ~ 0.7) as well as high accuracy in predicting synergy using four popular metrics (R2 ~ 0.9). Additionally, the model was able to predict a highly synergistic combination of Trametinib (MEK inhibitor) and Omipalisib (PI3K inhibitor) for TNBC treatment, which incidentally was recently in phase I clinical trials for TNBC. Our choice of tree-based models over networks for greater interpretability also allowed us to further interrogate which specific kinases were highly predictive of cell sensitivity in each cancer type, and we saw confirmatory strong predictive power in the inhibition of MAPK, CDK, and STK kinases. Overall, these results suggest that kinome inhibition states of kinase inhibitor combinations are strongly predictive of cell line responses and have great potential for integration into computational drug screening pipelines. This approach may facilitate the identification of effective kinase inhibitor combinations and accelerate the development of novel cancer therapies, ultimately improving patient outcomes.