Conclusion
Although the multifactorial and heterogeneous nature of cancer drug resistance remains a significant challenge, systematic experimental and clinical studies across many cancer types have revealed a wealth of resistance mechanisms. This review has proposed a convergence-based framework—pathway reactivation, pathway bypass, and pathway indifference—to organize the multiplicity of individual resistance mechanisms to targeted therapeutics into a parsimonious set of generalizable principles. Importantly, this framework may not prove comprehensive, nor is it intended to be proscriptive. Rather, it seems likely that additional as-yet unsuspected convergences will emerge. Nonetheless, the most fundamental lesson from such consideration may not be the identity of specific resistance convergences themselves, but rather that even highly complex landscapes of resistance can be understood through the paradigm of convergence. Going forward, such frameworks may provide both explanatory power to aid biological understanding and predictive power to guide future therapeutic approaches. Ultimately, these insights may help to achieve durable disease control in patients with advanced cancer.
