We extensively characterize drug hits in silico, demonstrating that they slow growth significantly in nine lung cancer cell lines from the NCl-60 collection, and identify CALM1 and PLA2G4A as promising drug targets for lung cancer.

Candidate therapeutics inhibit growth in nine NSCLC cell lines

As an independent validation of our results, we used growth inhibition data from the NCI-6O collection [18] to determine whether the drug candidates we identified are better at slowing growth in lung cancer cell lines .

For all our NCI-6O analyses we used the nine lung cancer cell lines in which over 100 Connectivity Map drugs were tested (see Methods).

One such resource, the Connectivity Map (CMap), which is the focus of our analyses, catalogues the transcriptional responses to drug treatment in human cell lines for over a thousand small molecules [3].

They tested one of their drug hits (17-AAG) in vitro and found that it inhibited growth in two lung adenocarcinoma cell lines .

This validation supported our method: drug candidates identified by CMapBatch were significantly more likely to slow growth in nine lung cancer cell lines than other CMap drugs.

This cell line differentiates into neurons and glial cells within 72 hours after growth factor removal, which might explain the faster time scale of our model compared to the Lee model.

Consequently our WNT/fi-catenin model is not only in agreement with data published earlier, but conclusions about WNT/fi-catenin signaling drawn from ReNcell VM197 cells do not appear to be cell line specific and, hence, seem generally applicable.

Indeed, earlier studies on the same cell line , provide eXperimental data, that show these dynamics for the early immediate cell response in untreated ReNcell VM197 cells: p-LRP6 was found to be NOT significantly increased during the early time points (0—3 hours), while fi-catenin shows the ascribed transient activation (cf.

Cross validation studies manifest its predictive capability for other cells and cell lines rendering the model a suitable basis for further studies also in the context of embryonic development, developmental disorders and cancers.

In a recent study with the same cell line , we uncovered an endogenous, WNT-independent activation of WNT/fi-catenin signaling through reactive oxygen species (ROS) in response to initiation of differentiation through growth-factor removal [21].

The ReNcell VM197 is a well-characterized cell line , that has been successfully applied in several studies and proven to be a simple and accepted model to investigate different aspects of neural differentiation [5, 8, 30—32].

The major advantage of this cell line is its rapid differentiation.

Our experimental results are retrieved from ReNcell VM 197 cells—a cell line , that is derived from the ventral midbrain of a 10-week-old human fetus and immortalized by retroviral transduction with v-Myc oncogene (ReNeuron Ltd, Guildford, UK).

The ReNcell VM197 cell line was derived from the ventral mesencephalon region of a human fetal brain tissue and is characterized by a rapid differentiation.

This implies that raft disruption serves as effective inhibitor for WNT/fi-catenin signaling in our cell line .