Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer

Maslov, Alexei A.; Trageser, Nicholas H.; Kichina, Julia V.; Elamir, Haya; Gardner, Evelyn; Teaman, Frances; Vishwanath, Vera; Dugas, Scott M.; Bianchi-Smiraglia, Anna; Leonova, Katerina I.; Gurova, Katerina V.; Nikiforov, Mikhail A.; Kandel, Eugene S.

doi:10.3390/ijms262411959

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Open AccessArticle

Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer

by

Alexei A. Maslov

¹,

Nicholas H. Trageser

¹,

Julia V. Kichina

²,

Haya Elamir

¹,

Evelyn Gardner

¹,

Frances Teaman

¹,

Vera Vishwanath

¹,

Scott M. Dugas

¹,

Anna Bianchi-Smiraglia

¹

,

Katerina I. Leonova

¹

,

Katerina V. Gurova

¹,

Mikhail A. Nikiforov

³ and

Eugene S. Kandel

^1,*

¹

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA

²

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA

³

Department of Pathology, Duke University, Durham, NC 27710, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(24), 11959; https://doi.org/10.3390/ijms262411959

Submission received: 26 October 2025 / Revised: 25 November 2025 / Accepted: 29 November 2025 / Published: 11 December 2025

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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Abstract

Despite continuing improvement in the standard of care, the clinical outcomes in metastatic colorectal cancer (CRC) remain poor, especially among patients whose tumors carry activating mutations in BRAF or RAS-family oncogenes. These mutations initiate a series of oncogenic signal transduction events, known as the mitogen-activated protein kinase (MAPK) cascade. While therapeutic targeting of this pathway achieved impressive results in other malignancies, the effectiveness of this approach remains low in CRC. In the current study, we observed that inhibitors of GTP production synergize with various inhibitors of the MAPK cascade in suppressing a variety of CRC cell lines. Furthermore, we discovered that an inhibitor of guanylate biosynthesis increases the efficacy of MAPK cascade inhibitors against human CRC grown in mice. Moreover, a combination of MEK and guanylate biosynthesis inhibitors is more potent than the MEK inhibitor alone in increasing the efficacy of immune therapy in an immunocompetent mouse model. Considering that guanylate biosynthesis inhibitors are already used in clinical practice for other applications, their use in synergistic combinations with the inhibitors of the MAPK cascade may present an actionable strategy to increase the efficacy of the latter.

Keywords: targeted therapy; colorectal carcinoma; mitogen-activated protein kinase

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MDPI and ACS Style

Maslov, A.A.; Trageser, N.H.; Kichina, J.V.; Elamir, H.; Gardner, E.; Teaman, F.; Vishwanath, V.; Dugas, S.M.; Bianchi-Smiraglia, A.; Leonova, K.I.; et al. Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer. Int. J. Mol. Sci. 2025, 26, 11959. https://doi.org/10.3390/ijms262411959

AMA Style

Maslov AA, Trageser NH, Kichina JV, Elamir H, Gardner E, Teaman F, Vishwanath V, Dugas SM, Bianchi-Smiraglia A, Leonova KI, et al. Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer. International Journal of Molecular Sciences. 2025; 26(24):11959. https://doi.org/10.3390/ijms262411959

Chicago/Turabian Style

Maslov, Alexei A., Nicholas H. Trageser, Julia V. Kichina, Haya Elamir, Evelyn Gardner, Frances Teaman, Vera Vishwanath, Scott M. Dugas, Anna Bianchi-Smiraglia, Katerina I. Leonova, and et al. 2025. "Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer" International Journal of Molecular Sciences 26, no. 24: 11959. https://doi.org/10.3390/ijms262411959

APA Style

Maslov, A. A., Trageser, N. H., Kichina, J. V., Elamir, H., Gardner, E., Teaman, F., Vishwanath, V., Dugas, S. M., Bianchi-Smiraglia, A., Leonova, K. I., Gurova, K. V., Nikiforov, M. A., & Kandel, E. S. (2025). Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer. International Journal of Molecular Sciences, 26(24), 11959. https://doi.org/10.3390/ijms262411959

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Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer

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