Hopes Revived for Targeting the "Undruggable" RAS Family

Jane de Lartigue, PhD
Published: Tuesday, Feb 11, 2014
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologThe members of the RAS oncogene family are central cogs in many different cell-signaling pathways, coordinate a variety of important cellular processes, and are highly mutated in a number of different cancers, including several with extremely poor prognosis. This makes them extremely attractive targets for anticancer therapy. However, over the course of more than a quarter of a century, the search for small-molecule inhibitors of RAS family members has proved fruitless. While a number of agents that indirectly target RAS have been developed, they have had limited success in patients with RAS mutations. Now, new strategies are offering hope that RAS may, in fact, be “druggable” after all.

The RAS Superfamily: A Molecular Switch

The RAS superfamily is a group of more than 150 genes that act as central nodes in cellular signaling networks, connecting a variety of upstream signals to an even larger array of downstream effector pathways to regulate cellular processes such as cell proliferation, survival, and death. The three “classical” RAS family members—KRAS, HRAS, and NRAS—sit on the inner face of cell membranes and cycle between two states in which they are either bound by guanosine diphosphate (GDP; the “off” state) or guanosine triphosphate (GTP; the “on” state). This switch is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which promote the formation of GDP-Ras and GTP-Ras, respectively. In the “on” state, they engage downstream effector proteins, including Raf kinase, phosphatidylinositol 3-kinase (PI3K), and RalGDS (guanine nucleotide dissociation stimulator), and transduce signals from cell membrane receptors such as the epidermal growth factor receptor (EGFR).

A Stuck Switch Leads to Cancer

As might be expected, a disruption to the delicate balance of Ras signaling is frequently implicated in the development of cancer. In fact, the RAS family are among the most commonly mutated genes in human cancer, particularly KRAS, which is mutated in 25% to 30% of all tumors and in up to 90% of pancreatic adenocarcinomas (Table). In both pancreatic and colorectal cancers, KRAS mutation is detected early in the progression of the disease, increases with the evolution of the tumor, and is strongly correlated with worse prognosis and increased aggressiveness of the tumor.

Table. Role of KRAS Mutations in Various Cancers

Tumor Type Reported Prevalence of KRAS Mutations1-6 Significance for Prognosis or Therapeutic Response
Biliary tract 35%
  • Predicts reduced survival rates7
Bladder 4%
  • No correlation reported8
Breast 4%
  • Predictive of grade 3 tumors9
Cervical 8%
  • Predicts significantly worse recurrence-free survival rates and associated with formation of distant metastases10
Colorectal 30%-40%
  • Predicts poor prognosis and increased aggressiveness
  • Multiple studies demonstrate reduced response to EGFR TKIs
  • NCCN guidelines recommend testing for KRAS mutation—only patients with wild-type KRAS should receive EGFR inhibitors
  • FDA-approved Therascreen KRAS PCR Kit for KRAS mutation testing1,2
Endothelium 15%
  • No data
Hematopoietic malignancies 5%-27%
  • Unclear1
Liver 6%
  • No data
- Large cell carcinoma
- Squamous cell carcinoma
- Adenocarcinoma
Small cell
  • Associated with inferior progression-free survival and response rates
  • Reduced response to EGFR TKIs and certain forms of chemotherapy1,2,11,12
- Ductal adenocarcinoma
- Endocrine tumor
85-95% (almost 100% in advanced cancer)
  • Predicts poor prognosis and increased aggressiveness (depending on KRAS mutation type)
  • Reduced response to EGFR TKIs1,2
Ovarian 14%
  • Significant association with mucinous histology, well-differentiated tumors, and positive progesterone expression13
  • May predict response to EGFR TKIs14
Prostate 8%
  • No data
Thyroid 2%-9%
  • Predicts poor survival15

Tumor types in bold are those in which most KRAS-directed research has been conducted.
EGFR TKIs indicates epidermal growth factor receptor tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer.
1Fernández-Medarde et al. Genes Cancer. 2011;2:344; 2Chetty et al. J Clin Pathol. 2013;66:548; 3Smit et al, Nucleic Acids Res.1988;16(16):7773; 4Almoguera et al. Cell.1988;53(4):549; 5Rodenhuis et al. Cancer Res.1992;52(9 suppl):2665s; 6Suda et al. Cancer Metastasis Rev. 2010;29(1):49; 7Malats et al. J Clin Oncol. 1995;13(7):1679; 8Ouerhani et al. Mol Biol Rep. 2013,40:4109; 9Pereira et al. PLoS One. 2013;8(3):e60576; 10Wegman et al. Int J Gynecol Cancer. 2011;21(1):86;11Sun et al. PLoS One. 2013;8(5):e64816;12Johnson et al. Cancer. 2013;119:356; 13Nodin et al. Diagn Path. 2013;8:106; 14Auner et al. BMC Cancer. 2009;9:111;15Garcia-Rostan et al. J Clin Oncol. 2003;21(17):3226.

Activating mutations in the RAS gene essentially keep the switch in the “on” position by preventing GAPs from associating with the Ras protein correctly and hydrolyzing GTP, so that Ras persists in its active GTP-bound state. In addition to mutations in RAS genes, the proteins can be inappropriately activated in other ways, such as via mutations in molecules that interact biochemically with Ras (including Kit and bcrabl) and, much more rarely, mutations in Ras GAPs (thus far, the only GAP implicated in tumorigenesis is NF-1).

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