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Does the recent RAS inhibitor data show that we can effectively treat RAS-related cancers?

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Does the recent RAS inhibitor data show that we can effectively treat RAS-related cancers?

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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 (for example, 15% of melanomas and 4% of head and neck cancer patients carry mutations in NRAS and HRAS, respectively).

The RAS protein family consists of low molecular weight guanosine 5-triphosphate (GTP, the building block of protein synthesis)-binding proteins that orchestrate a variety of cellular signaling networks. These pathways or networks 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 (continuously binding to GTP), which induces a pro-tumorigenic state characterized by unregulated cell proliferation and resistance to apoptosis (evading death signals). Constitutively activated RAS proteins trigger downstream signaling responsible for phenotypic traits known as hallmarks of cancer including: i) aberrant cell proliferation, ii) resistance to apoptosis (evasion of death signals), iii) increase in migration, cell invasion and metastasis to different tissues and iv) 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).

Exhibit 1. RAS signaling pathways involved in
human cancer

Source: Seminars in Cancer Biology 54 (2019) 138–148

RAS is an important therapeutic target, but is it a druggable
target?

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. Multiple clinical failures have led to the general perception that the oncogene RAS is “undruggable”.

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