Researchers at the University of Texas MD Anderson Cancer Center have identified a previously unknown relationship between the MYC protein and GSPT1 that creates a self-reinforcing cycle driving cancer growth. MYC activates the GSPT1 gene, while GSPT1 helps produce MYC proteins, forming what the study describes as a feed-forward loop. The findings were published in the journal Blood.
The experimental drug GT19630 is a dual protein degrader that binds to both MYC and GSPT1, marking MYC for disposal through the cell's natural protein recycling system while simultaneously degrading GSPT1. This mechanism differs from conventional inhibitors that attempt to block protein function directly.
In preclinical models of leukemia, lymphoma and multiple myeloma, GT19630 demonstrated strong anticancer activity. The therapy remained effective in cells carrying TP53 mutations, which are typically associated with treatment resistance and poor outcomes.
The degrader also showed promise against venetoclax-resistant acute myeloid leukemia (AML). Resistant AML cells exhibited elevated MYC and GSPT1 levels, and GT19630 restored sensitivity to venetoclax in preclinical models, extending survival by more than 300% in one model.
Single-cell RNA analysis revealed that stem-like AML cells, which can survive treatment and drive relapse, often contain higher MYC levels than normal blood-forming stem cells. TP53-mutant AML stem cells showed particular dependence on MYC, making them more sensitive to GT19630 while normal stem cells were less affected, suggesting a potential therapeutic window.
The study's lead authors, Michael Andreeff, M.D., Ph.D., and Yuki Nishida, M.D., Ph.D., note that MYC has been considered undruggable for decades because it lacks traditional binding pockets for small molecules. The protein degradation approach bypasses this limitation by harnessing cellular machinery to eliminate the protein entirely.
Researchers caution that these are preclinical findings and further studies are needed to determine safety and efficacy in patients. The results support evaluating GT19630 for resistant or relapsed AML, either as a direct treatment or in combination with other therapies, and suggest biomarkers could identify patients most likely to respond.
The protein degradation strategy demonstrated here may also expand the reach of targeted therapies against other challenging proteins previously considered beyond the scope of conventional drug development.
First-in-class therapy targets 'undruggable' protein in hard-to-treat blood cancers
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