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Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer

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Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer Published OnlineFirst June 3, 2014; DOI: 10.1158/1078-0432.CCR-13-1762 Clinical Cancer Review Research A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer Neil Vasan1, Julie L. Boyer2, and Roy S. Herbst3 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, Pded), 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. Clin Cancer Res; 20(15); 3921–30. Ó2014 AACR. Introduction sary for GTP hydrolysis (6), whereas G12 and G13 mutants Three RAS genes encode four proteins: HRas, KRas4a, prevent binding of Ras to its GAP and interfere with the KRas4b, and NRas (1). These proteins are GTPases, which orientation of Q61. These mutants result in Ras-GTP in an function as molecular switches: "on" when bound to GTP "on" state, driving oncogenesis (7; Fig. 1B). and "off" when bound to GDP. Ras-GTP can bind to The Ras proteins are important mediators of cell signal- numerous partner proteins, termed "effectors," and these ing. There is a wide range of Ras effector proteins, notably Ras-effector interactions lead to a cascade of downstream Raf (MAP kinase pathway), PI3K (Akt/mTOR pathway), signaling events (2). In normal cells, Ras signaling is crucial and RalGDS (Ral pathway). These effectors (which repre- for proliferation, differentiation, and survival (3). sent only a subset of downstream Ras signaling nodes) are The hydrolysis of GTP to GDP by Ras is a slow process, highly complex with numerous redundancies and interac- and therefore Ras cycles between these states with the aid of tions between pathways (8). Dysregulated Ras signaling regulatory proteins. GTPase-activating proteins (GAP) cat- results in increased proliferation, decreased apoptosis, dis- alyze the hydrolysis of GTP to GDP ("on to off"), whereas rupted cellular metabolism, and increased angiogenesis, all guanine nucleotide exchange factors (GEF) catalyze the seminal hallmarks of cancer (9; Fig. 1B). dissociation of GDP, with GTP binding afterward due to Ras Mutations: Differences from Isoform to its high concentration in cells ("off to on"; ref. 4; Fig. 1A). Amino Acid However, this pathway is co-opted by oncogenic muta- tions in Ras. Among the four Ras isoforms, the most RAS is the most commonly mutated oncogene in cancer (8), common mutations are at amino acid positions G12, with distinct Ras isoforms detected in various cancers (10). G13, and Q61 (5). Crystal structures of Ras proteins have KRas is the most commonly mutated isoform. Listed in order modeled these mutants’ mechanisms of activation. Q61 of percentage of cases, KRas mutations are most common in mutants prevent coordination of a water molecule neces- cancers of the pancreas, colon, biliary tract, and lung (the majority of which are adenocarcinomas); NRas mutations are most common in cancers of the skin (malignant melanoma) Authors' Affiliations: 1Department of Internal Medicine, Massachusetts and hematopoietic system (acute myeloid leukemia, AML); General Hospital, Boston, Massachusetts; 2The Sandra and Edward Meyer HRas mutations are most common in cancers of the head and Cancer Center at Weill Cornell Medical College, New York, New York; and 3Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New neck (squamous cell carcinoma) andurinarytract(transitional Haven, Connecticut cell carcinoma). Ras mutations are much less common in Corresponding Author: Roy S. Herbst, Yale University, 333 Cedar Street, cancers of the breast, central nervous system, or prostate WWW-221, New Haven, CT 06520. Phone: 203-785-6879; Fax: 203-737- (5; Fig. 2A). Why certain cancers seem to be driven preferen- 5698; E-mail: [email protected] tially by specific isoforms remains an outstanding question. doi: 10.1158/1078-0432.CCR-13-1762 Another unsettled issue in oncogenesis is the differential Ó2014 American Association for Cancer Research. role, if any, among different Ras-activating point mutations. www.aacrjournals.org 3921 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 3, 2014; DOI: 10.1158/1078-0432.CCR-13-1762 Vasan et al. AB RAS-GDP RAS-GDP GDP Pi GDP Pi GEF GAP GEF GAP GTP RAS-GTP GTP RAS*-GTP Figure 1. A, normal Ras signaling. B, oncogenic Ras signaling. When Effector RAF PI3K RALGDS Ras is mutated, it is constitutively bound to GTP such that its GAP cannot bind. The activated Ras signals through a multitude of effectors and downstream Normal signaling MEK AKT RAL signaling pathways, a subset of which is shown here. ERK mTOR RLIP Oncogenic signaling © 2014 American Association for Cancer Research CCR Reviews In lung cancer, the most common mutations are KRas Together, the in vitro, in vivo, and patient data suggest a G12C, G12V, and G12D (11). Other KRas-driven cancers greater oncogenic potential for KRas G12V (present in have different mutational frequencies: in the colon G12D, 20% of KRas-mutated lung cancers) compared with other G12V, and G13D; in the pancreas G12D, G12V, and G12R; mutations (18). and in the biliary tract G12D, G12V, and G12S (Fig. 2B). Unlike in HRas and NRas, KRas Q61 oncogenic mutations are very rare (7). Inhibiting Ras Membrane Association In vitro, KRas G12V and G12R have greater transform- A series of enzymes (Fig. 3), beginning with farnesyl- ing ability, as shown by soft agar colony formation (12). transferase (FTase), acts posttranslationally on the C-termi- Unexpectedly, there is no correlation between the GTPase nal C-A-A-X motif of Ras, resulting in the attachment to activity of the mutant and its propensity to transform membranes through cysteine prenylation (19). Next, Ras (13). However, once transformed, certain mutations are traffics to the endoplasmic reticulum, where its last three more aggressive than others. Mice with KRas G12V, amino acids are proteolyzed by Ras-converting enzyme G12R, and G12D had higher-stage lung tumors com- (RCE1), and then its C-terminus is methylated by isopre- pared with KRas G12C or wild-type (14). In patients nylcysteine carboxyl methyltransferase (ICMT; ref. 20). In with lung cancer, KRas G12C resulted in increased sen- the Golgi, HRas, NRas, and KRas4A are palmitoylated, and sitivity to pemetrexed and paclitaxel compared with the fully processed Ras then traffics to its final plasma G12V and G12D, although G12D patients were more membrane location (21). KRas4b is not palmitoylated but likely to respond to sorafenib (15). rather associates electrostatically with the membrane A recent retrospective analysis of the Biomarker-integrat- through a polybasic stretch in its C-terminus (22). Thus, ed Approaches of Targeted Therapy for Lung Cancer Elim- two modes of membrane association poise Ras isoforms for ination (BATTLE) clinical trial (16; discussed below) found activation and signaling. worse progression-free survival (PFS) for the group of patients with either KRas G12C or G12V, compared with FTase other KRas mutants, or wild-type [1.84 months vs. 3.35 Initial attempts to inhibit Ras focused on FTase (23). months (P ¼ 0.046), vs. 1.95 months; ref. 17]. KRas G12C These FTase inhibitors (e.g., lonafarnib, tipifarnib; ref. 24) and G12V had increased signaling through Ral and were oral medications, well tolerated, specific for FTase, and decreased signaling through Akt. This study suggests that were effective against HRas-transformed cells and HRas- targeted treatments and clinical trials in non–small cell lung driven murine tumors (25). However, these drugs did not cancer (NSCLC) may need to consider the specific KRas increase survival in clinical trials of patients with KRas- point mutation. mutated pancreatic cancer (26). Later studies found that 3922 Clin Cancer Res; 20(15) August 1, 2014 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 3, 2014; DOI: 10.1158/1078-0432.CCR-13-1762 A RAS Renaissance Figure 2. A, graph showing the percentage of cancers with Ras A mutations in different organ types, 60 arranged in descending KRAS frequency. KRas, NRas, and 50 HRas-driven cancers are denoted NRAS by color. The frequencies of the 40 HRAS predominant histology of that organ-specificKRas-mutated 30 cancer are listed below. For example, 17% of all lung cancers 20 have KRas mutations; of these with RAS mutations KRas-mutated lung cancers, 53% of cancers Percentage 10 are adenocarcinomas. These frequencies are likely 0 underestimates as many samples Pancreas Colorectal Biliary Lung Skin Hematologic Urinary Head and deposited into the COSMIC tract tract neck database are listed as a Frequency of 78% 91% 72% 53% 66% 42% 39% 69% "nonspecific" histology. Data were predominant Adenocarcinoma Melanoma AML Transitional Squamous accessed on May 15, 2013. B, pie histology cell carcinoma charts showing frequencies of different KRas mutations in KRas- B mutated lung, colorectal, pancreatic, and biliary tract G12V cancers. In all cancers, G12D and Lung Colorectal Pancreatic Biliary tract G12D G12V mutations are common; G12C however, each cancer displays a G12R different "KRas profile." In lung G12S cancer, G12C is the most common mutation, followed by G12V and G12A G12D.
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