A RAS renaissance: emerging targeted therapies for KRAS-mutated non-small cell lung cancer

Abstract

Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a "Ras renaissance," signified by new Ras and Ras pathway-targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non-small cell lung cancer as a case example.

Figure 1

Figure 1A: Normal Ras signaling. Figure 1B: Oncogenic Ras signaling. When Ras is mutated, it is constitutively bound to guanosine triphosphate (GTP) such that its GTPase activating protein (GAP) cannot bind. The activated Ras signals through a multitude of effectors and downstream signaling pathways, a subset of which is shown here. [GEF: Guanine nucleotide exchange factor]

Figure 2

Figure 2A: Graph showing the percentage of cancers with Ras mutations in different organ types, arranged in descending frequency. KRas, NRas, and HRas-driven cancers are denoted by color. The frequencies of the predominant histology of that organ-specific KRas-mutated cancer are listed below. For example, 53% of all lung cancers have KRas mutations; of these KRas-mutated lung cancers, 53% are adenocarcinomas. These frequencies are likely underestimates as many samples deposited onto COSMIC database are listed as a “nonspecific” histology. Data were accessed on May 15, 2013. Figure 2B: Pie charts showing frequencies of different Kras mutations in Kras-mutated lung, colorectal, pancreatic, and biliary tract cancers. In all cancers, G12D and G12V mutations are common; however each cancer displays a different “KRas profile.” In lung cancer, G12C is the most common mutation, followed by G12V and G12D; while in colorectal, pancreatic, and biliary tract cancers, G13D, G12R, and G12S are the third most common mutations, respectively, after G12D and G12V.

Figure 3

Ras processing, trafficking, membrane association, and inhibition. Ras is first farnesylated by farnesyltransferase (FTase). In the endoplasmic reticulum, it is proteolyzed by Ras converting enzyme (RCE1) and methylated by isoprenylcysteine carboxylmethyltransferase (ICMT). HRas, NRas, and KRas4a traffic to the Golgi where they are palmitoylated. Then they traffic to and associate with the plasma membrane. After depalmitoylation, these isoforms are chaperoned by PDE6δ and reaccumulate at the Golgi for another round of palmitoylation. KRas4b is chaperoned by PDE6δ and associates with the plasma membrane through its farnesyl group and electrostatically through a positively-charged patch. Membrane association of Ras isoforms is aided by farnesyl-binding membrane docking proteins. Relevant potential inhibitors are indicated in the figure.

Figure 3

Ras processing, trafficking, membrane association, and inhibition. Ras is first farnesylated by farnesyltransferase (FTase). In the endoplasmic reticulum, it is proteolyzed by Ras converting enzyme (RCE1) and methylated by isoprenylcysteine carboxylmethyltransferase (ICMT). HRas, NRas, and KRas4a traffic to the Golgi where they are palmitoylated. Then they traffic to and associate with the plasma membrane. After depalmitoylation, these isoforms are chaperoned by PDE6δ and reaccumulate at the Golgi for another round of palmitoylation. KRas4b is chaperoned by PDE6δ and associates with the plasma membrane through its farnesyl group and electrostatically through a positively-charged patch. Membrane association of Ras isoforms is aided by farnesyl-binding membrane docking proteins. Relevant potential inhibitors are indicated in the figure.