The Frequency of Ras Mutations in Cancer

Prior, Ian A.; Hood, Fiona E.; Hartley, James L.

doi:10.1158/0008-5472.can-19-3682

Cited by 641 publications

(620 citation statements)

References 55 publications

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“…Thus, we performed IFN-γ ELISPOT assays using peptides with a purity >90%; most importantly, cells were stimulated with the corresponding wt epitopes as negative controls in the ELISPOT wells. We chose to analyze responses to all epitopes from the codon 12 mutations, because they are the most frequent RAS mutations [ 14 , 29 ]. We also included high-purity epitopes from the G13R and G13V mutations, as they were the most immunogenic peptides in our initial analyses.…”

Section: Resultsmentioning

confidence: 99%

Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

Holmström

Andersen

2020

Cancers

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The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO+ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.

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Section: Resultsmentioning

confidence: 99%

Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

Holmström

Andersen

2020

Cancers

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“…The RAS-RAF interaction has taken center stage in cancer research as it is implicated in almost 20% of all known human cancers 30 . Direct protein-protein interaction between RAS and the Nterminal regulatory domain of RAF is critical for the recruitment of RAF to the plasma membrane, a crucial step in the process of RAS-mediated RAF activation 1,2 .…”

Section: Discussionmentioning

confidence: 99%

KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation

Tran

Chan

Young

et al. 2020

Preprint

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A vital first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we solved crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures revealed that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutation at the KRAS-CRD interface resulted in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.

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“…Dedicated technologies such as the second harmonic generation (SHG)-based screening method are sensitive to the orientation of a protein and may therefore enable specific drug screening campaigns for modulators of the Ras/ RAF conformation in the future [86] ( Table 1). [7] prohibitin inhibitors [87], salinomycin [88] Ras orientation RASopathies and cancer; mutations in Ras switch III [56,64] Cmpd 2 [81] Ras dimerization ? NS1 monobody [89]…”

Section: What Do We Know About the Activation Of Raf By Ras On The Mementioning

confidence: 99%

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Abankwa¹,

Gorfe²

2020

Preprint

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Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we will review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanocluster. We will discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We will then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we will show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/ neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization, while the whole Ras/ RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including, whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

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The Frequency of Ras Mutations in Cancer

Cited by 641 publications

References 55 publications

Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

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