Targeting the 'Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Feb 25

PMID 36831298

Authors

Kuen Kuen Lam

Siew Heng Wong

Peh Yean Cheah

Affiliations

Soon will be listed here.

Abstract

This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug-peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers.

Citing Articles

In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches.

Ajmal A, Danial M, Zulfat M, Numan M, Zakir S, Hayat C Pharmaceuticals (Basel). 2024; 17(5).

PMID: 38794122 PMC: 11124053. DOI: 10.3390/ph17050551.

Targeting KRAS Mutations: Discovery of Small Molecule Inhibitors for the Potential Treatment of Intractable Cancers.

Kargbo R ACS Med Chem Lett. 2023; 14(8):1041-1042.

PMID: 37583832 PMC: 10424306. DOI: 10.1021/acsmedchemlett.3c00277.

Unveiling New KRAS Inhibitors: A Promising Approach for Pancreatic Cancer Therapy.

Kargbo R ACS Med Chem Lett. 2023; 14(7):889-890.

PMID: 37465312 PMC: 10350939. DOI: 10.1021/acsmedchemlett.3c00222.

Discovery of Selective and Potent KRAS Inhibitors as Potential Therapy in Cancer.

Kargbo R ACS Med Chem Lett. 2023; 14(6):689-691.

PMID: 37312844 PMC: 10258824. DOI: 10.1021/acsmedchemlett.3c00167.

Targeted Degradation of KRAS as Potential Therapy in Cancer.

Kargbo R ACS Med Chem Lett. 2023; 14(5):537-538.

PMID: 37197464 PMC: 10184148. DOI: 10.1021/acsmedchemlett.3c00111.

References

Nomura T, Heishima K, Sugito N, Sugawara R, Ueda H, Yukihiro A . Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains. Cell Chem Biol. 2021; 28(11):1581-1589.e6. DOI: 10.1016/j.chembiol.2021.04.013. View

Hofmann M, Gerlach D, Misale S, Petronczki M, Kraut N . Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discov. 2022; 12(4):924-937. PMC: 9394389. DOI: 10.1158/2159-8290.CD-21-1331. View

Cox A, Fesik S, Kimmelman A, Luo J, Der C . Drugging the undruggable RAS: Mission possible?. Nat Rev Drug Discov. 2014; 13(11):828-51. PMC: 4355017. DOI: 10.1038/nrd4389. View

Stumpp M, Binz H, Amstutz P . DARPins: a new generation of protein therapeutics. Drug Discov Today. 2008; 13(15-16):695-701. DOI: 10.1016/j.drudis.2008.04.013. View

Teng K, Tsai S, Hattori T, Fedele C, Koide A, Yang C . Selective and noncovalent targeting of RAS mutants for inhibition and degradation. Nat Commun. 2021; 12(1):2656. PMC: 8113534. DOI: 10.1038/s41467-021-22969-5. View

Wherry E, Kurachi M . Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15(8):486-99. PMC: 4889009. DOI: 10.1038/nri3862. 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

Zhao Y, Xue J, Lito P . Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors. Cancer Discov. 2021; 11(1):17-19. DOI: 10.1158/2159-8290.CD-20-1331. View

Zhang J, Xiong H, Cao J, Wang S, Guo X, Lin B . A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway. Theranostics. 2018; 8(2):549-562. PMC: 5743566. DOI: 10.7150/thno.20047. View

10.

Mukhopadhyay S, Vander Heiden M, McCormick F . The Metabolic Landscape of RAS-Driven Cancers from biology to therapy. Nat Cancer. 2021; 2(3):271-283. PMC: 8045781. DOI: 10.1038/s43018-021-00184-x. View

11.

Plangger A, Rath B, Hochmair M, Funovics M, Hamilton G . Cytotoxicity of combinations of the pan-KRAS inhibitor BAY-293 against primary non-small lung cancer cells. Transl Oncol. 2021; 14(12):101230. PMC: 8488304. DOI: 10.1016/j.tranon.2021.101230. View

12.

Clark G, Drugan J, Terrell R, Bradham C, Der C, Bell R . Peptides containing a consensus Ras binding sequence from Raf-1 and theGTPase activating protein NF1 inhibit Ras function. Proc Natl Acad Sci U S A. 1996; 93(4):1577-81. PMC: 39983. DOI: 10.1073/pnas.93.4.1577. View

13.

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

14.

Tran T, Alexander P, Dharmaiah S, Agamasu C, Nissley D, McCormick F . The small molecule BI-2852 induces a nonfunctional dimer of KRAS. Proc Natl Acad Sci U S A. 2020; 117(7):3363-3364. PMC: 7035607. DOI: 10.1073/pnas.1918164117. View

15.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

16.

Stumpp M, Dawson K, Binz H . Beyond Antibodies: The DARPin Drug Platform. BioDrugs. 2020; 34(4):423-433. PMC: 7312107. DOI: 10.1007/s40259-020-00429-8. View

17.

Damnernsawad A, Kong G, Wen Z, Liu Y, Rajagopalan A, You X . Kras is Required for Adult Hematopoiesis. Stem Cells. 2016; 34(7):1859-71. PMC: 5358545. DOI: 10.1002/stem.2355. View

18.

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

19.

Leung E, Luo L, Liu Z, Wong V, Lu L, Xie Y . Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. Cell Death Dis. 2018; 9(2):216. PMC: 5833846. DOI: 10.1038/s41419-017-0065-9. View

20.

Barnard D, Sun H, Baker L, Marshall M . In vitro inhibition of Ras-Raf association by short peptides. Biochem Biophys Res Commun. 1998; 247(1):176-80. DOI: 10.1006/bbrc.1998.8746. View