Professor
Pauline and Stanley Foster Distinguished Chair
NCI-Designated Cancer Center
Why do recurrent cancers often exhibit resistance not only to prior treatments, but also to unrelated therapies? What is behind this “super-resistance” and how can we overcome it?
The “cancer cell autonomous” model posits that when cancer recurs, it is often more resistant to treatment because earlier therapies selectively killed sensitive cells but left behind rare resistant clones that repopulate the tumor.
It is thought that these surviving cells often have genetic or epigenetic changes that make them less responsive not only to the original treatment, but also to other drugs. Cancer evolves under treatment pressure over time, becoming more genetically diverse, activating alternative survival pathways, including sometimes adopting stem cell-like properties and increasing drug efflux and metabolism. Further improvement in single-cell technologies is needed to fully characterize these rare cells in human tumor samples.
Alternatively or additionally, changes in the tumor microenvironment (immune cells, blood vessels, fibroblasts….) can also contribute to drug resistance, making recurrent cancer harder to treat. The microenvironment can, for example, become immunosuppressive, hypoxic or fibrotic. These events can protect the cancer from immune attack, from drugs being metabolically active in the tumor or even from drugs physically entering the tumor proper. Better multi-cellular tumor models (tumoroids, organoids) and inter-disciplinary studies are required to understand the role of tumor microenvironment in drug resistance.
Once we understand better the causes for “super-resistance,” we can focus on preventing resistance through combination therapies, targeting resistant subclones and/or modifying the tumor microenvironment.