A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer
Open accessAbstract
Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS WT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RAS WT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCE: ADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.
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ADT-007 binds to the nucleotide-free form of RAS proteins, preventing GTP binding and subsequent RAS activation.
“It binds to the nucleotide-free form of RAS proteins, preventing GTP binding and subsequent RAS activation.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [100]
The selectivity of ADT-007 enables it to target mutant RAS in cancer cells without disrupting the function of WT RAS isoforms in normal cells, which is crucial for cell renewal and replacement in rapidly dividing tissues.
“This selectivity enables ADT-007 to target mutant RAS in cancer cells without disrupting the function of WT RAS isoforms in normal cells, which is crucial for cell renewal and replacement in rapidly dividing tissues [100].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [100]
RAS WT cancer cells harboring downstream BRAF mutations and normal cells are generally insensitive to ADT-007.
“In contrast, RAS WT cancer cells harboring downstream BRAF mutations and normal cells are generally insensitive to ADT-007.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [100]
ADT-007 inhibition leads to suppression of downstream signaling pathways, including MAPK and AKT, resulting in cell cycle arrest and apoptosis in cancer cells.
“This inhibition leads to the suppression of downstream signaling pathways, including MAPK and AKT, resulting in cell cycle arrest and apoptosis in cancer cells [100].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [100]
ADT-007 is a novel pan-RAS inhibitor that effectively suppresses the growth of RAS-mutant cancer cells, irrespective of the specific RAS mutation or isoform.
“ADT-007 is a novel pan-RAS inhibitor that effectively suppresses the growth of RAS-mutant cancer cells, irrespective of the specific RAS mutation or isoform.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [100]
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Self-citationRecent advances in therapeutic targeting of the KRAS pathway in cancer
Hitchen, N., Williams, S., & Desai, J. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108889 · Cited by 13 · see citing works
Gastrointestinal cancer: molecular pathogenesis and targeted therapy
Jin, Y., He, X., & Wu, Y. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00361-9 · Cited by 12 · see citing works
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Recent Anti-KRASG12D Therapies: A “Possible Impossibility” for Pancreatic Ductal Adenocarcinoma
Sobhani, N., Pittacolo, M., D’Angelo, A., & Marchegiani, G. (2025) · Cancers · doi:10.3390/cancers17040704 · Cited by 10 · see citing works
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Assessment of KRASG12C inhibitors for colorectal cancer
Piazza, G. A., Chandrasekaran, P., Maxuitenko, Y. Y., & Budhwani, K. I. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1412435 · Cited by 10 · see citing works
Self-citationAlanazi, F. E., Alatawi, Y. M., Alattar, A., Alshaman, R., Kotb, A. A., & Hetta, . F. (2025) · Pharmaceuticals · doi:10.3390/ph18121788 · Cited by 8 · see citing works
KRAS Inhibition in Pancreatic Ductal Adenocarcinoma
Pradeep, R., Isbeih, N. J., Abraham, F. F., Noori, E., Yeung, Z. P., & Kundranda, M. N. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15020873 · Cited by 8 · see citing works
Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C
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State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies
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Self-citationEvaluation of a Novel Pan-RAS Inhibitor in 3D Bioprinted Tumor Models
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Context defines precision: rethinking KRAS inhibition in oncology
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Genomic innovations in cancer prevention, diagnosis, prognosis and precision therapeutics
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Self-citationMediating kinase activity in Ras-mutant cancer: potential for an individualised approach?
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- Authors
- Foote, J. B., Mattox, T. E., Keeton, A. B., Chen, X., Smith, F., Berry, K. L., Holmes, T., Wang, J., Huang, C.-H., Ward, A. B., Mitra, A. K., Ramirez-Alcantara, V., Hardy, C., Fleten, K. G., Flatmark, K., Yoon, K. J., Sarvesh, S., Nagaraju, G. P., Bandi, D. S. R., Maxuitenko, Y. Y., Valiyaveettil, J., Carstens, J. L., Buchsbaum, D. J., Yang, J., Zhou, G., Nurmemmedov, E., Babic, I., Gaponenko, V., Abdelkarim, H., Boyd, M. R., Gorman, G. S., Manne, U., Bae, S., El-Rayes, B. F., & Piazza, G. A.
- Affiliations
- University of Alabama at Birmingham (US)
- University of South Alabama (US)
- University of Illinois Chicago (US)
- Auburn University (US)
- University of Connecticut (US)
- Augusta University (US)
- Corresponding author
- Piazza, Gary A.
- ORCID
- Foote, Jeremy B.
- Mattox, Tyler E.
- Keeton, Adam B.
- Chen, Xi
- Smith, Forrest
- Berry, Kristy L.
- Holmes, Thomas
- Huang, Chung-Hui
- Ward, Antonio B.
- Mitra, Amit K.
- Hardy, Cherlene
- Flatmark, Kjersti
- Yoon, Karina J.
- Sarvesh, Sujith
- Nagaraju, Ganji Purnachandra
- Bandi, Dhana Sekhar Reddy
- Carstens, Julienne L.
- Buchsbaum, Donald J.
- Yang, Jennifer
- Zhou, Gang
- Nurmemmedov, Elmar
- Gaponenko, Vadim
- Abdelkarim, Hazem
- Boyd, Michael R.
- Gorman, Gregory S.
- Manne, Upender
- Bae, Sejong
- Piazza, Gary A.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-05-19
- PMC
- PMC10849544
- OpenAlex
- W4377092453
- Cited by
- 13
- References
- 51
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Cancer Institute (R01CA238514, R01CA264983, R01CA254197)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- pan-RAS inhibitors, RAS mutations, BRAF mutation, UDP-glucuronosyltransferase, MAPK signaling, Akt signaling, mitotic arrest, apoptosis, colorectal cancer, pancreatic cancer, tumor immune microenvironment, antitumor immunity, prodrugs, oral bioavailability, drug resistance
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