Analysis of RAS as a tumor suppressor

Kenney, Chelsey; Stites, Edward C.

doi:10.1101/153692

“…Taken together, the data indicate that wildtype RAS inhibition of mutant RAS through direct dimerization likely represents an oversimplification of what is occurring in the context of the required membrane association needed for RAS function. Although many possible models have been proposed and discussed (49), precisely whether and how wild-type RAS functions as a tumor suppressor have not been definitively established.…”

Section: Discussionmentioning

confidence: 99%

Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

Li

¹

,

Lytle

²

,

Gammon

³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS–RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome–lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.

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“…The role of wild-type RAS isoforms is contradictory in tumours. While the biochemical properties and transforming potential of RAS oncoproteins suggest a dominant mechanism for these mutant proteins during tumorigenesis, several studies have argued for and against Article https://doi.org/10.1038/s41467-023-44342-4 the antagonising properties of wild-type RAS in the presence of oncogenic variants 18,33,34 . There is also evidence that this is context dependent based on the RAS isoform and the tissue type under investigation 35 .…”

Section: Discussionmentioning

confidence: 99%

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

Najumudeen,

Fey,

Millett

et al. 2024

Nat Commun

2

0

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Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.

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“…The role of wild-type RAS isoforms is contradictory in tumours. While the biochemical properties and transforming potential of RAS oncoproteins suggest a dominant mechanism for these mutant proteins during tumorigenesis, several studies have argued for and against the antagonizing properties of wild-type RAS in the presence of oncogenic variants 18,33,34 . There is also evidence that this is context dependent based on the RAS isoform and the tissue type under investigation 35 .…”

Section: Discussionmentioning

confidence: 99%

KRASallelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancerin vivo

Najumudeen,

Fey,

Millett

et al. 2023

Preprint

0

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OncogenicKRASmutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence ofKRASallelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele inKRASmutant cancers. However, there is still much debate over the function of wild-typeKRASin tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy ofKrasin the context of an intact oncogenicKrasin colorectal cancer. We observe that in the presence of oncogenicKras, wild-typeKrasacts to restrain tumour growth. Mechanistically, deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while presence of wild-typeKrasis associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-typeKrasin oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-typeKrasduring colon tumour initiation and highlights the critical impact of wild-typeKrasupon therapeutic response to MAPK and tumour progression inKrasmutant cancers.HighlightsWild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer modelsin vivoConcomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation.Wild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumoursLoss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models.

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Analysis of RAS as a tumor suppressor

Cited by 3 publications

References 41 publications

Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

KRASallelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancerin vivo

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