Highlights in Cancer Research: June 2024

Drug-tolerant persisters (DTPs) are a rare subset of cancer cells that evade death from targeted or chemotherapy by reversible withdrawal from the cell cycle through non-genetic mechanisms. Many studies have focused on the mechanisms through which DTP emerge, but far fewer studies have been directed at identifying the acquired vulnerabilities of DTPs. Such vulnerabilities could be exploited for their selective eradication to delay tumor relapse.

In this manuscript, Chen et al. used a kinome-based CRISPR screen and compound screen, to identify inhibition of bromodomain and extra-terminal domain (BET) proteins as a way to selectively reduce DTP populations across various cancer types. It was already known that DTPs have increased levels of Reactive Oxygen Species (ROS). The authors found that inhibition of BET proteins further increases ROS to toxic levels in DTPs through suppression of anti-oxidant genes like GPX2, ALDH3A1, and MGST1. In vivo experiments demonstrated that BET inhibitors effectively delayed tumor recurrence in melanoma and lung cancer models. In summary, the study by Chen et al. suggests that combining standard of care therapy with BET inhibitors to eliminate residual DTP cells is a promising therapeutic strategy.

Future impact

There are multiple related cell states that resemble DTPs, including senescence, dormancy, quiescence and diapause. Gold standard biomarkers to discriminate between these cell states are currently lacking. Finding the specific vulnerabilities of these different non-cycling cells through the approach used here may be a viable strategy to unambiguously identify these cells. For instance, using the same approach as described here, senescent cancer cells have been shown to be very sensitive to death receptor activation, while the current manuscript shows that DTPs are less responsive to this cell death trigger.