Clonal evolution and drug resistance: from cancer avatars to liquid biopsies.
A central paradigm of modern oncology is that tumor-specific molecular alterations underlie ‘functional’ dependencies that can be therapeutically exploited. Remarkable results have been obtained by applying this paradigm in the clinic, and several targeted drugs have been approved to treat, among others, melanomas, lung and colorectal cancers. Unfortunately, when metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Arguably, the rapid and apparently unavoidable emergence of resistance is the major limitation to further progress in the application of targeted therapies in oncology. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents?
We have used colorectal cancer (CRC) as a model system to test the hypothesis that the emergence of drug resistance can be controlled. To this goal, we studied how clonal evolution impacts the development of resistance in patients’ avatars (cell lines and tumor xenografts). In parallel, we analysed clonal evolution dynamics and drug resistance in the blood of patients (liquid biopsies) who received targeted therapies. Our results indicate that acquired resistance is -for the most part- a ‘fait accompli’. Mathematical models based on our data suggest that each (traceable) metastatic lesion contains hundreds of cells with mutations to virtually any targeted agents. According to this model, the time to relapse is simply the interval required for mutant or otherwise altered subclones to re-populate the lesion. On the positive side, we found that resistance can be prevented when drug combinations are rationally used.
Conclusions and perspectives:
The awareness that in nearly all patients targeted drugs are only transiently effective due to the rapid emergence of resistance poses a formidable challenge. Although the overall picture is looming, our data and the concepts they underlie offer several opportunities for intervention. Genetic tracking of cancer cell populations can be used to study how the development of resistance can be restrained in vitro and in vivo. Furthermore, liquid biopsies can be exploited to monitor clonal evolution and to intercept the emergence of resistant clones non-invasively in patients. When applied together cancer avatars and liquid biopsies may identify, monitor, and potentially overcome resistance to targeted therapies.