Drugging
the Undruggable: The War Against RAS Oncoproteins
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The RAS pathway is one of the most frequently dysregulated pathways in cancer. Approximately 30% of tumors harbor activating RAS gene mutations. There are three main isoforms of oncogenic RAS: KRAS, HRAS and NRAS. Among these genes, KRAS is the most frequently mutated (~90% of pancreatic cancers, ?35% of colon cancers). In comparison, NRAS and HRAS are mutated in a lesser number of cancer patients (15% of melanomas and 4% of head and neck cancer patients).
The RAS protein family consists of low molecular weight guanosine 5?-triphosphate (GTP), a building block of protein synthesis. GTP-binding proteins orchestrate a variety of cellular signaling networks, which are essential to regulate a variety of cellular functions including cell proliferation, differentiation, and cell survival. The three RAS proteins (N-RAS, H-RAS and K-RAS) oscillate between an active (GTP-bound) and an inactive (GDP-bound) state. When RAS genes are mutated (typically at codon 12, 13 or 61), RAS proteins are constitutively activated (i.e. continuously binding to GTP), which induces a pro-tumorigenic state characterized by unregulated cell proliferation and resistance to apoptosis (i.e. evading death signals). Constitutively activated RAS proteins trigger downstream signaling responsible for phenotypic traits known as hallmark of cancer including:
- aberrant cell proliferation
- resistance to apoptosis
- increase in migration, cell invasion and metastasis to different tissues
- escaping the anti-tumoral immune response
The phenotype of many cancer cells is determined by RAS-dependent aberrant signal transduction pathways involving various oncogenic proteins acting downstream of RAS (Exhibit 1).
The high mutational rate of RAS genes in cancer patients, combined with the fundamental role of RAS proteins in cancer biology, makes the RAS family of oncoproteins a primary therapeutic target. Since its discovery in 1982, both academia and industry have made significant efforts to develop an anti-cancer medicine targeting RAS. Despite these intensive efforts, there are no FDA approved anti-RAS drugs at present. For this reason, RAS is perceived as “undruggable”.
In 2013, the National Cancer Institute launched the “RAS
initiative” to expand efforts toward the discovery and development of novel medicines for the treatment of RAS-caused cancers. Since then, the initiative has focused on answering the key questions:
- Can it be targeted directly or indirectly?
- Which effector pathway of RAS is most crucial for cancer initiation and progression?
- Are specific mutants or isoforms required to be specifically targeted for effective inhibition?
The enthusiasm generated by the “RAS initiative” has sparked renewed interest by the biotech and pharma industries, which has restarted their own RAS programs.
Exhibit
1. RAS signaling pathways involved in human cancer
Source:
Seminars in Cancer Biology 54 (2019) 138–148
