Abstract
Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.
Highlights
Ras proteins are the founding members of the Ras superfamily of GTPases, which in humans is composed of more than 150 members [1,2]
In the last few years, our capacity to study the in vivo ramifications of the expression of oncogenic Ras has been constantly improving due to the development of sophisticated genetically engineered mouse models that feature activating mutations of Ras
We know that activation of K-Ras on cancer cells reshapes the tumor microenvironment, both by oncogenic signaling coming from tumor cells affecting other cells of the stroma, and by normal signaling within stromal cells
Summary
Ras proteins are the founding members of the Ras superfamily of GTPases, which in humans is composed of more than 150 members [1,2]. Three Ras genes (H-ras, N-ras, and K-ras) encode four distinct Ras proteins: H-Ras, N-Ras, K-Ras4A, and K-RasS4B, the latter 2 resulting from alternative RNA splicing of the K-ras gen. These four Ras isoforms are ubiquitously expressed and are highly similar in primary sequence, structure, and biochemical properties [5,6]. They share 90% sequence identity in the G domain [7], being 100% identical in the N-terminus of this domain, termed the effector lobe, and sharing 82% of the sequence of the allosteric lobe [5,8]. The frequency in which every isoform appears mutated varies by tissue type: a large percentage of adenocarcinoma of the lung (32%), pancreas (86%), and colon (41%) is driven by K-Ras mutations; 29% of melanomas are driven by mutations in N-Ras, while H-Ras mutations appears mutated in 5% of head and neck squamous cell carcinoma and 6% of bladder cancers [11]
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