‘Two-in-one’ RNA molecule can simultaneously turn off two difficult-to-target cancer-related genes

University of North Carolina Lineberger Comprehensive Cancer Center researchers have developed a “two-in-one” molecule that can simultaneously turn off two notoriously difficult-to-target cancer-related genes, KRAS and MYC, as well as directly deliver drugs to tumors that express these genes. This advance holds special promise for treating cancers that have been historically challenging to treat.

The new technology incorporates novel compositions of inverted RNAi molecules that have shown a marked ability to co-silence mutated KRAS and over-expressed MYC. RNA interference (RNAi) is a cellular process that uses small interfering RNAs (siRNAs) to selectively turn off, or silence, mutated genes. The co-silencing resulted in an up to a 40-fold improvement in inhibition of cancer cell viability compared to the use of individual siRNAs.

The laboratory findings were published in the Journal of Clinical Investigation on July 31.

“Targeting two cancer-causing genes at the same time is akin to slicing both Achilles heels of cancer, which has tremendous potential,” said Chad V. Pecot, MD, corresponding author of the article, professor of medicine at UNC School of Medicine. “Our inverted molecule establishes proof-of-concept for dual-silencing of KRAS and MYC in cancer and constitutes an innovative molecular strategy for co-targeting not just those two genes, but any two genes of interest, which has broad implications.”

Mutated KRAS and MYC can work together to promote and maintain aggressive tumor development through several mechanisms, including stimulation of inflammation, activation of cancer cell survival pathways and suppression of cancer cell death.

KRAS mutations are present in nearly 25% of all human cancers, and they frequently occur in some of the most prevalent tumor types. MYC is also regarded as a critical cancer-related gene and is dysfunctional in approximately 50-70% of cancers. Several studies have shown that inactivation of MYC can substantially inhibit tumor development, making it a very attractive therapeutic co-target.

“MYC seems to be nearly as important a target as KRAS, however there are still no successful drugs capable of targeting MYC,” said 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 at the same time. We have also made the first ‘two-in-one’ molecule capable of silencing both the KRAS and MYC proteins.”

Because most cancers depend on multiple genetic mutations, or drivers, for survival, this technology is especially valuable for targeting two key drivers at once. It holds particular promise when both targets, like MYC and KRAS, are critical to the cancer cell’s ability to stay alive but have historically been difficult to treat with drugs. Pecot noted that the unique features of their design make it possible to begin exploring the ability to silence three targets at one time. “The opportunities are vast,” he says.

This discovery builds on a related finding from Pecot’s lab published in Cancer Cell in June, which described a targeted drug delivery mechanism for a specific KRAS variant known as KRAS G12V. Now, Pecot and his colleagues have developed an RNA silencing molecule capable of shutting down all KRAS mutations found in cancer.

While this broader approach is less specific than the earlier KRAS G12V-targeted method, it has the potential to treat a much larger group of patients, including those with the most common KRAS mutations found in lung, colorectal, and pancreatic cancers. Together, these cancers are expected to account for nearly half a million new cases in the U.S. this year, according to the American Cancer Society.

“Overall, this is another nice example of RNA therapeutics being made at UNC as part of the RNA Discovery Center,” Pecot said. “These advances could bring real hope to patients with KRAS-related cancers.”