About the RAS/RAF/MEK/ERK Pathway
A range of cell-surface molecules activate RAS (KRAS, NRAS, and HRAS), a family of GTPases that act as molecular switches, turning on the downstream RAF protein kinases (BRAF, CRAF, and ARAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1 and MEK2. MEK kinases appear to have only one main substrate, ERK (also called mitogen-activated protein kinase or MAPK). This chain of proteins, from RAS to ERK, communicates signals from cell-surface receptors to the DNA. ERK generates extensive changes in gene expression mediated by transcription factors that control cell cycle progression, differentiation, protein synthesis, metabolism, cell survival, cell migration, and invasion and senescence. In fact, activation of ERK leads to cells acquiring many of the hallmarks of cancer, and targeting the pathway has been seen as an attractive option to overcome the malignant phenotype.
Quick RAS facts:
- Mutations in RAS proteins that lead to activation of RAF kinases are the most common oncogenes, present in approximately 30% of human cancers.
- Three million new cancers are diagnosed worldwide every year with RAS mutations, including
both solid tumor and hematologic malignancies.
- Mutated RAS proteins are also the most potent of human oncogenes, leading to changes that, along with other events, can transform normal cells into malignant cancer cells.
- RAS mutations are most frequent in pancreatic cancer (90%), colorectal cancer (40%), non–small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%).
- Mutations in the RAF isoform BRAF, present in 6% of human cancers and responsible for approximately 500,000 new cancers per year, are also highly oncogenic in combination with other genetic events and capable of transforming normal cells to cancer cells.
It is no wonder that targeting RAS mutations has attracted the interest of the pharmaceutical industry.
Targeting the RAS/RAF/MEK/ERK Pathway
Although the GTPase RAS itself has not been successfully targeted directly with a small molecule therapy, the BRAF protein kinase has been successfully targeted directly with a number of BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib [formerly LGX818]) with striking clinical results. The most common mutation in BRAF is V600E, accounting for more than 85% of the BRAF mutations in melanoma, more than 50% of the mutations in non–small cell lung cancer, and more than 95% of mutations in colorectal cancer, cholangiocarcinoma, and hairy cell leukemia.
MEK inhibition has also been effective in treating patients with the V600E BRAF mutation in melanoma. Patients with melanoma receiving the MEK inhibitor trametinib showed tumor regression and better overall survival in comparison with patients randomly selected to receive dacarbazine. However, response rates for trametinib (22%) were lower than those observed for BRAF inhibitors vemurafenib, dabrafenib, or encorafenib (approximately 40%-60%), probably because of an inability to elevate doses of the MEK inhibitor because of adverse events.
An interesting feature of BRAF inhibition is a difference in signaling between normal and malignant cells, which contributes to the selectivity of BRAF inhibitors for mutant versus wild-type kinases. This allows inhibition of signaling in malignancies harboring V600 mutations in BRAF with relatively limited effects on signaling in normal cells.
Two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib) have been approved by U.S. regulators for the treatment of BRAF-mutated melanoma, clinically validating the ability of RAS/RAF/MEK pathway inhibition to achieve meaningful benefit for patients. However, questions and challenges remain.
The chief question is whether the pathway can be targeted to achieve clinically meaningful outcomes in patients with RAS-mutated cancers. Response to first-generation MEK inhibitors in RAS-mutated cancer was modest (< 10%) and may be insufficient to achieve clinically meaningful results. The RAF inhibitor sorafenib does not have significant activity in RAS-mutated cancers. ERK inhibitors are in clinical development, but toxicity may be a hindrance to achieving efficacy. Combination therapy may be the best approach to adequately inhibit this pathway in cells and tumors with RAS mutations.
Future Prospects: Targeting RAS
The most common mechanism of acquired resistance to BRAF inhibitors in BRAF-mutated melanoma is the acquisition of new genomic events that reactivate MEK and ERK signaling. This has led to the idea that resistance may be overcome or prevented by more effective targeting of the pathway.
The chief approach to achieving better inhibition of the pathway has been with combinations of type 1 BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib). The combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib have shown activity in patients acquiring resistance to single-agent BRAF inhibition, and dabrafenib plus trametinib was shown to be superior to single-agent dabrafenib in delaying the emergence of resistance, leading to U.S. regulatory approval for this combination last year.
The ability to inhibit the same pathway at two points, as with this combination, may not only lead to greater inhibition of the pathway though additive effects but may also affect feedback mechanisms in a favorable way. Notably, the dabrafenib plus trametinib combination appears to be associated with less toxicity than single-agent dabrafenib.
It has been postulated that MEK inhibitors may have activity in RAS-mutated cancers. However, results have been disappointing, with low response rates. Recent data have suggested that feedback activation of MEK may limit activity of MEK inhibitors in RAS-mutated cancers. If so, this approach could lead to the development of the first effective targeted approach for the treatment of RAS-driven malignancy.
Another approach to target mutant RAS is inhibition of multiple pathways activated by RAS, such as with a combination of MEK and PI3K inhibition. However, toxicity from this combined-pathway approach is substantial. The MEK and PI3K pathways have diverse roles in normal cells, with little crosstalk between pathways. Still, RAS-mutated cells might be more sensitive to combined inhibition of these pathways compared with normal cells, and the combination approach deserves further attention.
Rapid advances have been made in strategies to target signaling in the RAS/RAF/MEK/ERK pathways using small molecules, fundamentally changing the approach to treatment of cancers with applicable mutations. Despite these major advances, particularly in targeting of BRAF mutations, it will be desirable to more effectively target this pathway, with efforts to reduce toxicity and improve efficacy. The ultimate goal remains the successful targeting of RAS-mutated cancers.