Targeting the "undruggable" RAS - new strategies - new hope?

Britta Mörchen; Oleksandr Shkura; Raphael Stoll; Iris Helfrich

doi:10.20517/cdr.2019.21

Targeting the "undruggable" RAS - new strategies - new hope?

Cancer Drug Resist. 2019 Sep 19;2(3):813-826. doi: 10.20517/cdr.2019.21. eCollection 2019.

Authors

Britta Mörchen^{1

2}, Oleksandr Shkura³, Raphael Stoll^{3

4}, Iris Helfrich^{1

2

4}

Affiliations

¹ Skin Cancer Unit of the Dermatology Department, Medical Faculty, University Duisburg-Essen, West German Cancer Center, Essen 45147, Germany.
² German Cancer Consortium (DKTK) partner site Düsseldorf/Essen, Essen 45147, Germany.
³ Biomolecular NMR, Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Bochum D-44780, Germany.
⁴ Both authors contribute equally.

Abstract

K-RAS is the most frequently mutated oncogene in solid tumors, such as pancreatic, colon or lung cancer. The GTPase K-RAS can either be in an active (GTP-loaded) or inactive (GDP-loaded) form. In its active form K-RAS forwards signals from growth factors, cytokines or hormones to the nucleus, regulating essential pathways, such as cell proliferation and differentiation. In turn, activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP (GTPase-activating) - and GEF (Guanine nucleotide exchange factor) - proteins, driving neoplastic transformation. Due to a rather shallow surface, K-RAS lacks proper binding pockets for small molecules, hindering drug development over the past thirty years. This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression, giving new hope for future treatments of K-RAS mutated cancer.

Keywords: K-RAS; PD-1; PD-L1; immune checkpoints; small molecules.

Publication types

Review