Chad Pecot, Full Professor at UNC Chapel Hill and Director of UNC RNA Discovery Center, shared on LinkedIn:
“What’s better than drugging one “undruggable” target? Drugging 2 at the same time!
Now out in JCI, our group reports the development of the first dual KRAS+MYC inhibitor
Key Highlights:
- We developed potent, drug-like pan-KRAS and MYC RNAi molecules.
- Using an endonucleolytic bridge, we created an “inverted chimera” capable of co-targeting pan-KRAS and MYC.
- Inverted chimeras resulted in marked improvement in potency over single-targeting siRNAs, which we found to be due to 5’ anti-sense dT overhangs.
- Pharmaco-kinetic and -dynamic profiling demonstrated that chimeras are metabolically more stable and accumulate more readily than single siRNAs, resulting in significant dual suppression of KRAS and MYC.
- KRAS/MYC inverted chimeras demonstrated significant anti-tumor activity in lung, colon, and pancreatic cancer models, with significant improvements over individual pan-KRAS and MYC RNAi.
- KRAS/MYC inverted chimeras could overcome acquired pan-RAS inhibitor (RMC-7977) resistance through potent targeting of MYC, demonstrated in vitro and in vivo.
- KRAS/MYC chimera-treated tumors can develop acquired resistance through activation of the YAP pathway.
This was a massive effort spanning many years, led by newly minted Dr. Yogitha Chareddy, PhD. I’m also very grateful to the hard work of my lab and excellent collaborators, Martin Egli and Albert Bowers.
Thanks so much to the reviewers who helped make the paper more robust and challenged us to go in new directions. I’m also grateful for funding sources from National Cancer Institute (NCI), Lung Cancer Initiative North Carolina Biotechnology Center (NCBiotech), UNC Lineberger Comprehensive Cancer Center, EnFuego Therapeutics.”
Title: Inverted chimeric RNAi molecules synergistically co-target MYC and KRAS in KRAS-driven cancers
Authors: Yogitha S Chareddy, Hayden P. Huggins, Snehasudha S Sahoo, Lyla Stanland, Christina Gutierrez-Ford, Kristina M. Whately, Lincy Edatt, Salma H Azam, Matthew C. Fleming, Jonah Im, Alessandro Porrello, Imani Simmons, Jillian L. Perry, Albert A. Bowers, Martin Egli, Chad V. Pecot
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