Developing a Mixed Cell Model to Capture Prostate Cancer Heterogeneity
Chemotherapy is a standard tool for the treatment of all cancers, which can be done through treatment with monotherapy with a single drug or combination therapy with multiple drugs. In the past, the main hypothesis for the increased efficacy of combination therapy was thought to be drug synergy, but models using synergy for combination prediction have not panned out well in clinical settings. Thus, the more relevant theory may be independent drug action, which is a model that hypothesizes that combination therapy works by each drug separately inhibiting cell populations that respond differentially to each drug. While there is some promising clinical evidence for this model, pre-clinical in vitro research has thus far been very limited, and an in vitro model that mimics tumor heterogeneity is needed in order to progress combination therapy research. Here we show the development of a tumor heterogeneity model using a cancer cell co-culture. We labeled 3 transcriptionally heterogeneous prostate cancer cell lines and found that in co-culture they did not exhibit any unexpected interactions. Testing with two differentially predicted efficacious combination drugs showed that in a mixed cell model, the predicted efficacious model showed a benefit of combination chemotherapy while the predicted non-efficacious model did not. From these results we conclude that the use of co-culturing in modeling tumor heterogeneity is valid and using it to validate combination chemotherapies is possible as a step to screen for future drug combinations for study in vivo and in clinical trials.