Development of combination cancer therapies is widely thought to be the key to improving rates of response and reducing the likelihood of acquired resistance, and indeed multi-drug combinations can produce curative outcomes in some cancers. Contemporary combination therapies are commonly developed based on pre-clinical evidence of drug synergy. Here I present two studies of several clinically successful combination therapies that identify the control of within-tumour and between-tumour heterogeneity, irrespective of drug synergy, as critical contributors to efficacious combination therapy.
Though analysing between-patient variability in drug response in clinical trials, I show that independent drug action is sufficient to explain the superiority of many FDA-approved combinations, and combinations tested in patient-derived xenografts. In the independent action model, an individual patient benefits only from the drug to which their tumour is most sensitive with no benefit from the less effective drug. Independent drug action can confer clinically significant benefit because responsiveness to single drugs varies dramatically from patient to patient and because responses to different drugs are only partially correlated. Independent action provides an alternative interpretation of existing trial data and suggests design principles for new combination therapies.
Undoubtedly some combinations can surpass independent action, most obviously demonstrated by curative outcomes. To characterize an exemplar of curative combination therapy I studied the treatment of diffuse large B-cell lymphoma (DLBCL) by R-CHOP (rituximab, cytoxan, doxorubicin, vincristine, prednisone). Isobologram analysis revealed that these therapies are at best additive; none interact synergistically. High-complexity DNA barcoding was employed to profile resistance and cross-resistance in 1 million DLBCL subclones, revealing that each drug faces prolific pre-existing resistance but no subclone is cross-resistant to all drugs, suggesting that the success of RCHOP lies in the eradication of drug resistance.
Together, these studies identify the management of between-tumour and within-tumour heterogeneity as key features of effective drug combinations, and yield analytical and experimental platforms for the identification of novel combinations with these traits.