Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: In contrast to organismal evolution, human cancers are subjected to similar initial conditions and follow a limited range of possible evolutionary trajectories. Therefore, the repetitive nature of cancer evolution may prove to be its greatest weakness. Evolutionary trajectories of clear cell renal cell carcinoma (ccRCC) have been recently described. In this review, we will discuss the relevance of estimating the trajectory of ccRCC evolution as a readout for a response to therapy. Next, we will propose strategies to take advantage of the evolving nature of these tumors for patients’ benefit. ABSTRACT: The emergence of clinical resistance to currently available systemic therapies forces us to rethink our approach to clear cell renal cell carcinoma (ccRCC). The ability to influence ccRCC evolution by inhibiting processes that propel it or manipulating its course may be an adequate strategy. There are seven deterministic evolutionary trajectories of ccRCC, which correlate with clinical phenotypes. We suspect that each trajectory has its own unique weaknesses that could be exploited. In this review, we have summarized recent advances in the treatment of ccRCC and demonstrated how to improve systemic therapies from the evolutionary perspective. Since there are only a few evolutionary trajectories in ccRCC, it appears feasible to use them as potential biomarkers for guiding intervention and surveillance. We believe that the presented patient stratification could help predict future steps of malignant progression, thereby informing optimal and personalized clinical decisions.