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New Research Identifies BET Inhibitors as Key to Overcoming Cancer Therapy Resistance
The IHI-funded PERSIST-SEQ consortium has developed workflows that allow for a standardized approach by which knowledge of identification and targeting of drug-tolerant persisters (DTPs) in cancer can be translated into better diagnostics and therapeutics for patients.
An exciting study from members of the PERSIST-SEQ consortium highlights novel insights into overcoming therapy resistance by targeting DTPs. In many cases, cancer treatments initially work, often leading to remission, however there remains a significant percentage of patients who relapse. A major culprit are DTPs, a small, rare subpopulation of cells lying dormant within a tumor. When cancer treatment is gradually phased out or stopped, these cells can re-start growth and re-populate the tumor, causing relapse. Through collaboration within the consortium, a team of researchers from the group of René Bernards showed that DTPs have vulnerabilities and can be selectively targeted, potentially without harmful side-effects.
Modeled and validated in lung and melanoma cancer cell cultures, Bernards and team showed that targeting the vulnerabilities in DTPs could delay or prevent tumor relapse, and combining standard of care therapy with this selective targeting could prove to be a promising therapeutic strategy. Using CRISPR-Cas9 technology and drug screens, the study found a specific gene, coding for a BRD protein, that is a critical vulnerability of DTPs as it is essential for their survival. Targeting this gene with a BET inhibitor was effective at killing DTPs across cell-based models of multiple cancer types, significantly delaying tumor growth, both after initial therapy and when given in combination with conventional treatment.
Also, through collaboration within the consortium, the study identified different subtypes of DTPs using single-cell RNA sequencing, with some undergoing very slow cell division and others not dividing at all. These findings offer a proof of concept that targeting DTPs can contribute to overcoming one of the major hurdles in cancer treatment, relapse. Upcoming efforts within PERSIST-SEQ aim to validate the findings of Bernards and team in animal models of various cancer types.
This study marks a successful milestone and highlights the value of PERSIST-SEQ as a unique platform using cutting-edge single cell RNA sequencing technology, with standardization of samples and a universal methodology, to understand cancer biology and inform therapeutic strategies, promote collaboration, and invariably improve outcomes for cancer patients.