Abstract:
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we un-
derstand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and
development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief
among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously
understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as
well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there
are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known con-
tributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell
plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to
be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of
cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as
cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of
CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different
subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical
oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated
and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug
discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.
