Absolute Quantification of Endogenous Ras Isoform Abundance

Mageean, Craig J.; Griffiths, John R.; Smith, Duncan L.; Clague, Michael J.; Prior, Ian A.

doi:10.1371/journal.pone.0142674

Cited by 35 publications

(41 citation statements)

References 45 publications

(49 reference statements)

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“…The notion that KRas protein expression is limited contrasts with quantitation of Ras isoform protein abundance in cancer cell lines where KRas was the most abundant isoform in the majority of cell lines1541. Our analysis of Ras isoform gene expression in normal tissues is broadly consistent with the dominance of KRas protein expression in cancer cell lines representing a wide range of tissues; however, the relative proportions are significantly different.…”

Section: Discussionsupporting

confidence: 61%

Quantification of spatiotemporal patterns of Ras isoform expression during development

Newlaczyl

Coulson

Prior

2017

Sci Rep

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Ras proteins are important signalling hubs frequently dysregulated in cancer and in a group of developmental disorders called Rasopathies. Three Ras genes encode four proteins that differentially contribute to these phenotypes. Using quantitative real-time PCR (qRT-PCR) we have measured the gene expression profiles of each of the Ras isoforms in a panel of mouse tissues derived from a full developmental time course spanning embryogenesis through to adulthood. In most tissues and developmental stages we observe a relative contribution of KRas4B > > NRas ≥ KRas4A > HRas to total Ras expression with KRas4B typically representing 60–99% of all Ras transcripts. KRas4A is the most dynamically regulated Ras isoform with significant up-regulation of expression observed pre-term in stomach, intestine, kidney and heart. The expression patterns assist interpretation of the essential role of KRas in development and the preponderance of KRas mutations in cancer.

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Section: Discussionsupporting

confidence: 61%

Quantification of spatiotemporal patterns of Ras isoform expression during development

Newlaczyl

Coulson

Prior

2017

Sci Rep

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“…This suggests that the levels of KRAS, NRAS, and HRAS are similar between the isogenic cell lines. This is also consistent with pervious proteomic characterization of these cells (16).…”

Section: Kras G12c Binds Less Well To the Crafsupporting

confidence: 92%

“…To investigate whether the EGFR inhibitor cetuximab might have activity on KRAS G12C CRC we first utilized a panel of isogenic CRC cells derived from the SW48 colon cancer cell line. Through homologous recombination, multiple derivative cell lines are available that have one KRAS allele replaced with a KRAS mutant allele (14)(15)(16). We performed cetuximab dose responses on SW48 KRAS WT cells, as well KRAS G12C, KRAS G12V, and KRAS G12D derivative isogenics.…”

Section: Heterozygous Mutant Kras G12c Crc Cells Are Sensitive To Egfmentioning

confidence: 99%

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

McFall

Trogdon

Sisk-Hackworth

et al. 2019

Preprint

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Multiple KRAS G12C inhibitors are in development, and the identification of effective combination treatment regimens should maximize the benefit these agents have on cancer patients. Here, we find that KRAS G12C heterozygous mutated colorectal cancer cells are sensitive to targeting with EGFR therapeutic antibodies. We find that KRAS G12C is partially impaired in binding to tumor suppressor NF1 and also to RAF, and our computational simulations reveal how these deficiencies result in partial sensitivity to EGFR inhibition. For the combination of EGFR and G12C inhibitors we observe synergy and reductions in active forms of both wild-type and mutant RAS. Our simulations reveal the synergy involves both wild-type and mutant RAS. Overall, our work suggests that the addition of an EGFR inhibitor to a KRAS G12C inhibitor regimen should be further evaluated as a strategy for KRAS G12C colorectal cancer patients.

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“…This question is highly significant, since CaM interacts only with K-Ras; but not with the other Ras isoforms, H-Ras or N-Ras [1–7]. K-Ras is among the most frequently mutated oncogenes in human tumors [8–12], particularly in pancreatic (almost 100%), lung (35%), and colorectal (45%) cancers [13, 14]. K-Ras has two alternative splicing variants: K-Ras4A and the most abundant K-Ras4B.…”

Section: The Puzzle Of Calmodulin’s Critical Action In Kras-driven Camentioning

confidence: 99%

Calmodulin and PI3K Signaling in KRAS Cancers

et al. 2017

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Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras. Our up-to-date review discusses CaM’s role in PI3K signaling at the membrane in KRAS-driven cancers. This is significant since it may help development of K-Ras-specific pharmacology.

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Absolute Quantification of Endogenous Ras Isoform Abundance

Cited by 35 publications

References 45 publications

Quantification of spatiotemporal patterns of Ras isoform expression during development

Quantification of spatiotemporal patterns of Ras isoform expression during development

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

Calmodulin and PI3K Signaling in KRAS Cancers

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