A first-in-class EGFR-directed KRAS G12V selective inhibitor

Lyla J Stanland¹, Hayden P Huggins², Snehasudha S Sahoo³, Alessandro Porrello³, Yogitha Chareddy⁴, Salma H Azam⁵, Jillian L Perry⁶, Pradeep S Pallan⁷, Kristina Whately³, Lincy Edatt³, William D Green⁸, Matthew C Fleming⁹, Jonah Im², Christina Gutierrez-Ford⁵, Imani Simmons⁵, Alyaa Dawoud³, Katherine I Zhou¹⁰, Vandanaa Jayaprakash², Rani S Sellers¹¹, Gabriela de la Cruz¹¹, Albert Wielgus¹¹, Justin Milner⁸, Martin Egli⁷, Albert A Bowers¹², Chad V Pecot¹³

Affiliations

¹ EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA.
² EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA; Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; Center for Nanotechnology in Drug Delivery, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁹ Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA; Center for Integrative Chemical Biology and Drug Discovery, Chapel Hill, NC, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Medical Oncology, Duke University, Durham, NC 27705, USA.
¹¹ Department of Pathology and Laboratory Medicine, UNC at Chapel Hill, Chapel Hill, NC, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA; Center for Integrative Chemical Biology and Drug Discovery, Chapel Hill, NC, USA; Department of Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Hematology/Oncology, UNC at Chapel Hill, Chapel Hill, NC, USA. Electronic address: pecot@email.unc.edu.

PMID: 40541192
PMCID: PMC12230742 (available on 2026-06-19)
DOI: 10.1016/j.ccell.2025.05.016

A first-in-class EGFR-directed KRAS G12V selective inhibitor

Lyla J Stanland et al. Cancer Cell. 2025.

. 2025 Oct 13;43(10):1815-1832.e10.

doi: 10.1016/j.ccell.2025.05.016. Epub 2025 Jun 19.

Authors

Affiliations

¹ EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA.
² EnFuego Therapeutics, Inc, Morrisville, NC 27560, USA; Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; Center for Nanotechnology in Drug Delivery, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, UNC at Chapel Hill, Chapel Hill, NC, USA.
⁹ Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA; Center for Integrative Chemical Biology and Drug Discovery, Chapel Hill, NC, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Medical Oncology, Duke University, Durham, NC 27705, USA.
¹¹ Department of Pathology and Laboratory Medicine, UNC at Chapel Hill, Chapel Hill, NC, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA; Center for Integrative Chemical Biology and Drug Discovery, Chapel Hill, NC, USA; Department of Chemistry, UNC at Chapel Hill, Chapel Hill, NC, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, UNC at Chapel Hill, Chapel Hill, NC, USA; Division of Hematology/Oncology, UNC at Chapel Hill, Chapel Hill, NC, USA. Electronic address: pecot@email.unc.edu.

PMID: 40541192
PMCID: PMC12230742 (available on 2026-06-19)
DOI: 10.1016/j.ccell.2025.05.016

Abstract

Despite KRAS^G12V being the second most common KRAS mutation in cancer, no direct inhibitors targeting KRAS^G12V have been approved. RNA interference (RNAi) has faced numerous obstacles as cancer therapeutic, including the lack of cancer-specific tissue targeting, rapid oligonucleotide nuclease degradation, and clearance from circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs have shown remarkable promise in circumventing these barriers. In this study, we demonstrate that an EGFR-directed RNAi molecule (EFTX-G12V) is highly selective for KRAS^G12V and exhibits improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. Using a targeted RNAi delivery platform, we achieve effective tumor silencing of KRAS^G12V and significant anti-tumor activity across several cancer models. Our findings represent a technological advance in oncogene targeting using RNAi and provide new biologic insights in KRAS targeting with potential implications for safety and efficacy.

Keywords: EGFR; KRAS; RNA interference; angiogenesis; cancer; ligand conjugation; lung cancer; mutant-selective; siRNA; siRNA delivery.

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Conflict of interest statement

Declaration of interests C.V.P., S.H.A., Y.S.C., M.C.F., A.A.B., and C.V.P. hold intellectual property interests on this work. C.V.P. is founder of EnFuego Therapeutics, Inc. and holds equity in the company. L.J.S., H.P.H., V.J., and J.I. were employees of EnFuego Therapeutics at the time of this work. S.S.S., A.P., J.L.P., P.S.P., K.W., L.E., W.D.G., C.G-F., I.S., A.D., K.I.Z., R.S.S., G.D.L.C., A.W., J.M., and M.E. declare no competing interests.

References

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A first-in-class EGFR-directed KRAS G12V selective inhibitor

Affiliations

A first-in-class EGFR-directed KRAS G12V selective inhibitor

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous