FDA-approved drug sensitises brain cancer cells to radiotherapy

MRI showing glioblastoma

Researchers have discovered a clinical drug that sensitises glioblastoma (GBM) cells to radiotherapy and could replace the current standard of care. 

Scientists from Korea and the US have unveiled the mechanism of radioresistance in GBM cells, identifying therapeutic targets to overcome radioresistance. 

GBM is a WHO grade IV brain tumour with dismal prognosis. Although post-surgical radiation chemotherapy combined with temozolomide is the standard line of treatment, GBM cells surviving radiotherapy contribute to tumour progression and recurrence even more aggressively.  

The team, led by Professor BuHyun Youn from Pusan National University in Korea, has unveiled a plausible mechanism underlying the radioresistance of GBM cells that involves regulating an internal steady state of lipid within the cells, known as “lipid homeostasis.” 

“Put simply, radioresistant GBM cells prefer to stock up on fatty acids instead of utilising them as an energy source in order to reduce mitochondrial reactive oxygen species that may cause damage to their DNA, RNA, and proteins, and, in turn, cell death,” explains Prof Youn. 

The research process

In their study, published in Cell Reports Medicine, the researchers derived GBM stem cells from patients and established radioresistant cells for investigation.  

They showed that diacylglycerol kinase B (DGKB), a regulator of the intracellular level of diacylglycerol (DAG), was significantly suppressed in radioresistant GBM cells. This, in turn, increased DAG accumulation and decreased fatty acid oxidation, reducing mitochondrial lipotoxicity (harmful lipid accumulation in non-adipose tissues) in GBM cells and contributing to their radioresistance.  

Further, the team showed that the ionising radiation induced an increase in the level of diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyses the formation of triglycerides from DAG. 

Armed with this understanding, the researchers further demonstrated that the genetic inhibition of DGAT1 suppresses radioresistance. In addition, they discovered that cladribine, a clinical drug, activates DGKB and inhibits DGAT1. This action sensitised GBM cells to radiotherapy both in vitro and in vivo (in mouse models). 

“Our research has revealed cladribine as a radiosensitiser for GBM treatment by drug repurposing, which can offer multiple advantages,” says Prof Youn. “As an FDA-approved oral drug, the side-effects of cladribine are quite manageable and it has been well evaluated for pharmacokinetics. Additionally, the clinical trial period will be considerably shorter than that required for new drug development. In this regard, cladribine could become a standard future treatment for GBM.” 

Taken together, this study demonstrates that DGKB and DGAT1 are potential therapeutic targets for overcoming GBM radioresistance. Moreover, drugs like cladribine could potentially replace existing treatment options with a new and more effective strategy. 

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