Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS

by Selleckchem | Jul 06 2023

RAS proteins (HRAS, KRAS, NRAS) participate in many physiological signal transduction processes related to cell growth, division, and survival. The RAS proteins are small (188/189 amino acid residues) and they function as GTPases. These proteins toggle between inactive and functional forms; the conversion of inactive RAS-GDP to active RAS-GTP as mediated by guanine nucleotide exchange factors (GEFs) turns the switch on and the intrinsic RAS-GTPase activity stimulated by the GTPase activating proteins (GAPs) turns the switch off. RAS is upstream to the RAS-RAF-MEK-ERK and the PI3-kinase-AKT signaling modules. Importantly, the overall incidence of RAS mutations in all cancers is about 19% and RAS mutants have been a pharmacological target for more than three decades. About 84% of all RAS mutations involve KRAS. Except for the GTP/GDP binding site, the RAS proteins lack other deep surface pockets thereby hindering efforts to identify high-affinity antagonists; thus, they have been considered to be undruggable. KRAS mutations frequently occur in lung, colorectal, and pancreatic cancers, the three most deadly cancers in the United States. Studies within the last decade demonstrated that the covalent modification of KRAS C12, which accounts for about 10% of all RAS mutations, led to the discovery of an adjacent pocket (called the switch II pocket) that accommodated a portion of the drug. This led to the development of sotorasib as a second-line treatment of KRASG12C-mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

Comments:

Yes, you have provided an accurate overview of RAS proteins and their involvement in various cellular processes. RAS proteins, including HRAS, KRAS, and NRAS, play critical roles in signal transduction pathways that regulate cell growth, division, and survival. They act as GTPases, toggling between inactive (RAS-GDP) and active (RAS-GTP) forms.

The activation of RAS-GTP is facilitated by guanine nucleotide exchange factors (GEFs), which promote the exchange of GDP for GTP, thereby turning the RAS switch "on." Conversely, the intrinsic GTPase activity of RAS is stimulated by GTPase activating proteins (GAPs), leading to the hydrolysis of GTP to GDP and turning the RAS switch "off."

RAS proteins are upstream regulators of important signaling modules, including the RAS-RAF-MEK-ERK pathway and the PI3-kinase-AKT pathway. Dysregulation of these pathways due to RAS mutations can contribute to cancer development and progression. In fact, RAS mutations are found in approximately 19% of all cancers, with KRAS mutations being the most prevalent (accounting for about 84% of all RAS mutations).

Traditionally, developing high-affinity antagonists for RAS proteins has been challenging due to the lack of deep surface pockets, aside from the GTP/GDP binding site. This characteristic has made RAS proteins historically difficult to target with small molecule inhibitors, leading to their reputation as "undruggable" targets.

However, recent advances have shed light on potential therapeutic strategies for targeting RAS mutations, particularly KRAS mutations. Studies have revealed that covalent modification of KRAS C12, which represents around 10% of all RAS mutations, uncovered an adjacent pocket known as the switch II pocket. This discovery provided an opportunity to develop inhibitors that can bind to this pocket. Notably, sotorasib has emerged as a second-line treatment for KRASG12C-mutant non-small cell lung cancer, specifically targeting this mutation.

Additionally, considerable effort has been devoted to developing inhibitors that target downstream components of the RAS signaling pathways, such as MAP kinase (MEK) inhibitors and PI3-kinase inhibitors. By blocking these pathways, these indirect RAS antagonists aim to disrupt the aberrant signaling caused by RAS mutations.

Overall, while RAS proteins have long been considered challenging targets for drug development, recent breakthroughs have shown promise in developing therapeutic interventions against RAS mutations, particularly KRAS mutations. These advancements offer hope for improving treatment options for cancers associated with RAS pathway dysregulation.