Two-in-One RNA: Silencing Two Cancer Genes Simultaneously
New ‘Two-in-One’ Molecule Concurrently Targets KRAS and MYC in Cancer Cells
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Researchers at the University of North Carolina (UNC) Lineberger Extensive Cancer Center have developed a novel RNA silencing molecule capable of simultaneously targeting two critical cancer-driving genes: KRAS and MYC. This breakthrough offers a promising new therapeutic strategy for cancers that rely on both genes for survival, particularly those resistant to conventional treatments.The findings, published in the Journal of Clinical Examination, represent a significant step forward in RNA therapeutics and could potentially benefit hundreds of thousands of patients annually.
The challenge of Targeting KRAS and MYC
KRAS mutations are among the moast common in human cancers, appearing in roughly 25% of all cases and frequently driving the growth of prevalent tumor types like lung, colorectal, and pancreatic cancers. MYC, often described as a critical cancer-related gene, is dysfunctional in an even larger proportion – approximately 50-70% – of cancers. Inactivating MYC has demonstrated considerable tumor-inhibiting effects, making it a highly desirable therapeutic target.
Though, despite their importance, directly targeting these genes with conventional drugs has proven exceptionally tough. KRAS has historically been considered “undruggable” due to it’s smooth molecular surface, lacking ideal binding sites for small molecule inhibitors. While progress has been made in targeting specific KRAS variants, like KRAS G12V, a broader approach is needed. MYC also presents significant challenges, lacking a clear structural pocket for drug binding.”MYC seems to be nearly as vital a target as KRAS, however there are still no successful drugs capable of targeting MYC,” explains Dr. charles Pecot, co-leader of the UNC Lineberger Cancer Therapeutics Program and director of the UNC RNA Discovery Center. ”Our study is one of the first to deeply characterize the therapeutic implications of targeting both genes simultaneously occurring. We have also made the first ‘two-in-one’ molecule capable of silencing both the KRAS and MYC proteins.”
A Novel RNA Silencing Approach
The UNC research team developed an “inverted chimeric RNAi molecule” designed to simultaneously silence both KRAS and MYC expression. RNA interference (RNAi) is a natural biological process where RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules. This new molecule leverages this process to effectively shut down both target genes.
This strategy is particularly valuable because most cancers aren’t driven by a single mutation, but rather a combination of genetic drivers. By targeting two key drivers simultaneously, the new molecule overcomes potential resistance mechanisms that might arise if only one gene were targeted. Dr. Pecot notes the design’s flexibility, suggesting the possibility of expanding the approach to silence three targets at once, opening up even broader therapeutic avenues.
Building on Previous KRAS Research
This discovery builds upon earlier work from Dr. Pecot’s lab, published in Cancer cell in June, which focused on a targeted drug delivery mechanism for the KRAS G12V variant. The current research expands this approach to encompass all KRAS mutations found in cancer.
While the earlier method was highly specific to KRAS G12V, this broader approach has the potential to treat a significantly larger patient population, including those with the most common KRAS mutations found in lung, colorectal, and pancreatic cancers. The American Cancer Society estimates these three cancers alone will account for nearly half a million new cases in the U.S. this year.
Implications for Cancer Treatment and Future Research
The advancement of this dual-targeting RNA silencing molecule represents a significant advancement in RNA therapeutics. The ability to simultaneously disrupt two critical cancer pathways offers a powerful new strategy for overcoming treatment resistance and improving patient outcomes.”this is another nice example of RNA therapeutics being made at UNC as part of the RNA Discovery Center,” says Dr. Pecot.”These advances could bring real hope to patients with KRAS-related cancers.”
Further research will focus on optimizing the delivery of this molecule to tumor cells and evaluating its efficacy in preclinical models. The team is also exploring the potential to expand the technology to target additional cancer-driving genes, paving the way for personalized cancer therapies tailored to the unique genetic profile of each patient’s tumor.
Source:
University of North Carolina Health Care. [https://www.unchealth.org/home](https://www.unchealth.