Targeting the "undruggable" RAS with Biologics

Overview

Journal Adv Cancer Res

Publisher Elsevier

Specialty Oncology

Date 2022 Feb 1

PMID 35101232

Authors

Michael Whaby

Imran Khan

John P OBryan

Affiliations

Soon will be listed here.

Abstract

RAS proteins represent critical drivers of tumor development and thus are the focus of intense efforts to pharmacologically inhibit these proteins in human cancer. Although recent success has been attained in developing clinically efficacious inhibitors to KRAS, there remains a critical need for developing approaches to inhibit additional mutant RAS proteins. A number of anti-RAS biologics have been developed which reveal novel and potentially therapeutically targetable vulnerabilities in oncogenic RAS. This review will discuss the growing field of anti-RAS biologics and potential development of these reagents into new anti-RAS therapies.

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References

Grimm S, Lundberg E, Yu F, Shibasaki S, Vernet E, Skogs M . Selection and characterisation of affibody molecules inhibiting the interaction between Ras and Raf in vitro. N Biotechnol. 2010; 27(6):766-73. DOI: 10.1016/j.nbt.2010.07.016. View

Hobbs G, Baker N, Miermont A, Thurman R, Pierobon M, Tran T . Atypical KRAS Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer. Cancer Discov. 2019; 10(1):104-123. PMC: 6954322. DOI: 10.1158/2159-8290.CD-19-1006. View

Vidimar V, Beilhartz G, Park M, Biancucci M, Kieffer M, Gius D . An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth. Proc Natl Acad Sci U S A. 2020; 117(29):16938-16948. PMC: 7382267. DOI: 10.1073/pnas.2000312117. View

Tay R, Richardson E, Toh H . Revisiting the role of CD4 T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 2020; 28(1-2):5-17. PMC: 7886651. DOI: 10.1038/s41417-020-0183-x. View

Shin S, Choi D, Jung K, Bae J, Kim J, Park S . Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nat Commun. 2017; 8:15090. PMC: 5436137. DOI: 10.1038/ncomms15090. View

Fell J, Fischer J, Baer B, Blake J, Bouhana K, Briere D . Identification of the Clinical Development Candidate , a Covalent KRAS Inhibitor for the Treatment of Cancer. J Med Chem. 2020; 63(13):6679-6693. DOI: 10.1021/acs.jmedchem.9b02052. View

Stocks M . Intrabodies: production and promise. Drug Discov Today. 2004; 9(22):960-6. DOI: 10.1016/S1359-6446(04)03269-6. View

Biancucci M, Minasov G, Banerjee A, Herrera A, Woida P, Kieffer M . The bacterial Ras/Rap1 site-specific endopeptidase RRSP cleaves Ras through an atypical mechanism to disrupt Ras-ERK signaling. Sci Signal. 2018; 11(550). PMC: 6309442. DOI: 10.1126/scisignal.aat8335. View

Yang J, Liu D, Zhen S, Zhou Y, Zhang D, Yang L . A novel anti-p21Ras scFv antibody reacting specifically with human tumour cell lines and primary tumour tissues. BMC Cancer. 2016; 16:131. PMC: 4761205. DOI: 10.1186/s12885-016-2168-6. View

10.

Tanaka T, Rabbitts T . Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth. Oncogene. 2010; 29(45):6064-70. DOI: 10.1038/onc.2010.346. View

11.

Leshchiner E, Parkhitko A, Bird G, Luccarelli J, Bellairs J, Escudero S . Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci U S A. 2015; 112(6):1761-6. PMC: 4330742. DOI: 10.1073/pnas.1413185112. View

12.

Sakamoto K, Kamada Y, Sameshima T, Yaguchi M, Niida A, Sasaki S . K-Ras(G12D)-selective inhibitory peptides generated by random peptide T7 phage display technology. Biochem Biophys Res Commun. 2017; 484(3):605-611. DOI: 10.1016/j.bbrc.2017.01.147. View

13.

Koide A, Wojcik J, Gilbreth R, Hoey R, Koide S . Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. J Mol Biol. 2011; 415(2):393-405. PMC: 3260337. DOI: 10.1016/j.jmb.2011.12.019. View

14.

Nilsson F, Tolmachev V . Affibody molecules: new protein domains for molecular imaging and targeted tumor therapy. Curr Opin Drug Discov Devel. 2007; 10(2):167-75. View

15.

Kwak J, Jeong H, Satchell K . Vibrio vulnificus rtxA1 gene recombination generates toxin variants with altered potency during intestinal infection. Proc Natl Acad Sci U S A. 2011; 108(4):1645-50. PMC: 3029691. DOI: 10.1073/pnas.1014339108. View

16.

Khan I, Spencer-Smith R, OBryan J . Targeting the α4-α5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene. 2018; 38(16):2984-2993. PMC: 6474814. DOI: 10.1038/s41388-018-0636-y. View

17.

Lu R, Hwang Y, Liu I, Lee C, Tsai H, Li H . Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020; 27(1):1. PMC: 6939334. DOI: 10.1186/s12929-019-0592-z. View

18.

Traxlmayr M, Kiefer J, Srinivas R, Lobner E, Tisdale A, Mehta N . Strong Enrichment of Aromatic Residues in Binding Sites from a Charge-neutralized Hyperthermostable Sso7d Scaffold Library. J Biol Chem. 2016; 291(43):22496-22508. PMC: 5077188. DOI: 10.1074/jbc.M116.741314. View

19.

Werge T, Baldari C, Telford J . Intracellular single chain Fv antibody inhibits Ras activity in T-cell antigen receptor stimulated Jurkat cells. FEBS Lett. 1994; 351(3):393-6. DOI: 10.1016/0014-5793(94)00892-2. View

20.

Hunter J, Manandhar A, Carrasco M, Gurbani D, Gondi S, Westover K . Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res. 2015; 13(9):1325-35. DOI: 10.1158/1541-7786.MCR-15-0203. View