RAS: Striking at the Core of the Oncogenic Circuitry

Abstract

Cancer is a devastating disease process that touches the lives of millions worldwide. Despite advances in our understanding of the genomic architecture of cancers and the mechanisms that underlie cancer development, a great therapeutic challenge remains. Here, we revisit the birthplace of cancer biology and review how one of the first discovered oncogenes, RAS, drives cancers in new and unexpected ways. As our understanding of oncogenic signaling has evolved, it is clear that RAS signaling is not homogenous, but activates distinct downstream effectors in different cancer types and grades. RAS signaling is tightly controlled through a series of post-transcriptional mechanisms, which are frequently distorted in the context of cancer, and establish key metabolic and immunologic states that support cancer growth, migration, survival, metastasis, and plasticity. While targeting RAS has been fiercely pursued for decades, new strategies have recently emerged with the potential for therapeutic efficacy. Thus, understanding the complexities of RAS biology may translate into improved therapies for patients with RAS-driven cancers.

Keywords: RAS; cancer; cancer therapy; immunology; metabolism; mitogen activated kinase.

Figure 1

RAS pathway in cancer. This diagram demonstrates (1) the upstream activators of RAS signaling (2) regulators of RAS membrane localization, (3) regulators of RAS activity, (4) downstream signaling effector pathways, and (5) downstream functional effects of RAS signaling in cancers.

Figure 2

Epidemiology of RAS alterations in cancer. (A) Frequency of KRAS alterations across a number of cancer types. Data were derived from Cerami et al. (33) and Gao et al. (34). (B) Frequency of NRAS alterations across a number of cancer types. Data were derived from Cerami et al. (33) and Gao et al. (34). (C) Frequency of HRAS alterations across a number of cancer types. Data were derived from Cerami et al. (33) and Gao et al. (34). (D) Localization of RAS gene mutations across the gene body. Data were derived from Cerami et al. (33) and Gao et al. (34). (E) Prognosis of cancer patients with or without alterations in KRAS, NRAS, or HRAS. Data were derived from Cerami et al. (33) and Gao et al. (34).

Figure 3

Gene pair co-occurrence among RAS pathway genes. (A) Co-occurrence plot RAS pathway genes across a number of cancer types. Data were derived from Cerami et al. (33) and Gao et al. (34). (B) Gene pair co-occurrence plot of RAS pathway genes. Blue bars indicate gene pairs that are significantly mutually exclusive, red bars indicate gene pairs that are significantly co-occurrent, and black bars indicate gene pairs without significant co-occurrence. (C) Gene pair co-occurrence network. Solid blue lines indicate gene pairs that are significantly mutually exclusive, solid red lines indicate gene pairs that are significantly co-occurrent, and dotted lines indicate gene pairs without significant co-occurrence.

Figure 4

The RAS pathway orchestrates cellular metabolism. This diagram depicts metabolic pathways that are altered in RAS-driven cancers.

Figure 5

The RAS pathway shapes interactions between cancer cells and the immune microenvironment. This diagram depicts mechanisms by which RAS signaling promotes cancer through (1) supporting cancer cell immune evasion and (2) driving immune-mediated stimulation of cancer cell growth.

Figure 6

Therapeutic targeting of RAS in cancer. This diagram depicts several strategies to therapeutically target RAS driven cancers.