Targeting the “undruggable” RAS - new strategies - new hope?

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.

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

“…Lonafarnib was approved for the therapy of progeria (Hutchinson-Gilford progeria syndrome and progeroid laminopathy) [43]. In addition to FTase inhibitors, the direct inhibition of Ras proteins offers promising starting points for the development of potent Ras signaling suppressors [44].…”

The Ras dimer structure

“…1,[10][11][12][13] Currently, there is no drug against constitutively active Ras approved and Ras is traditionally referred to as undruggable. Recently, with advancing methods and new targeting concepts, progress has been made in identifying the drug attacking points of Ras 14,15 and Ras targeting drug development. 16 This progress has led to the rst drug; however its effects are restricted to the G12C mutation 17,18 that is e.g.…”