Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation

Murphy, Brandon; Terrell, Elizabeth M.; Chirasani, Venkat R.; Weiss, Tirzah J.; Lew, Rachel E.; Holderbaum, Andrea M.; Dhakal, Aastha; Posada, Valentina; Fort, Marie; Bodnar, Michael S; Carey, L.M.; Chen, Min; Burd, Craig J.; Coppola, Vincenzo; Morrison, Deborah K.; Campbell, Sharon L.; Burd, Christin E.

doi:10.1038/s41467-022-30881-9

Cited by 16 publications

(25 citation statements)

References 71 publications

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“…Mice similarly exhibit a bias of specific oncogenic Kras mutations towards different cancer types as different mutant Kras alleles have different tumorigenic potential when activated in different tissues ( Li et al, 2018 ; Poulin et al, 2019 ; Winters et al, 2017 ; Wong et al, 2020 ; Zafra et al, 2020 ). Different oncogenic mutations also affect the ability of Nras to induce tumorigenesis in mice, as do the same mutations in different RAS isoforms ( Burd et al, 2014 ; Haigis et al, 2008 ; Kong et al, 2016 ; Murphy et al, 2022 ). While this tissue ‘tropism’ of cancers towards specific RAS mutations has been appreciated for decades ( Bos, 1989 ), the underlying mechanism is unclear.…”

Section: Introductionmentioning

confidence: 99%

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis

Roux

Pershing

Kaltenbrun

et al. 2022

eLife

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Despite multiple possible oncogenic mutations in the proto-oncogene KRAS, unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being the initiating event, these mutational biases are ostensibly a product of how normal cells respond to the encoded oncoprotein. Oncogenic mutations can impact not only the level of active oncoprotein, but also engagement with proteins. To attempt to separate these two effects, we generated four novel Cre-inducible (LSL) Kras alleles in mice with the biochemically distinct G12D or Q61R mutations and encoded by native (nat) rare or common (com) codons to produce low or high protein levels. While there were similarities, each allele also induced a distinct transcriptional response shortly after activation in vivo. At one end of the spectrum, activating the KrasLSL-natG12D allele induced transcriptional hallmarks suggestive of an expansion of multipotent cells, while at the other end, activating the KrasLSL-comQ61R allele led to hallmarks of hyperproliferation and oncogenic stress. Evidence suggests that these changes may be a product of signaling differences due to increased protein expression as well as the specific mutation. To determine the impact of these distinct responses on RAS mutational patterning in vivo, all four alleles were globally activated, revealing that hematolymphopoietic lesions were permissive to the level of active oncoprotein, squamous tumors were permissive to the G12D mutant, while carcinomas were permissive to both these features. We suggest that different KRAS mutations impart unique signaling properties that are preferentially capable of inducing tumor initiation in a distinct cell-specific manner.

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Section: Introductionmentioning

confidence: 99%

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis

Roux

Pershing

Kaltenbrun

et al. 2022

eLife

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“…We used the TN 61R , TN 61L , TN 61K , and TN 13R mouse models to generate NRAS-mutant melanoma cell lines syngeneic to C57BL/6J (Murphy et al, 2022). Each mouse model is homozygous for a melanocyte-specific Cre-ER(T2) transgene (which was not certified by peer review) is the author/funder.…”

Section: Resultsmentioning

confidence: 99%

“…We used the TN 61R , TN 61L , TN 61K , and TN 13R mouse models to generate NRAS-mutant melanoma cell lines syngeneic to C57BL/6J (Murphy et al, 2022). Each mouse model is homozygous for a melanocyte-specific Cre-ER(T2) transgene (Tyr::Cre-ER(T2); (Bosenberg et al, 2006)) and a conditional LSL-Nras allele encoding either NRAS Q61R, Q61K, Q61L, or G13R ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…F, Immunoblot of protein lysates isolated from the OSUMMER cell lines. Note that melanoma-associated NRAS codon 61 mutants are known to migrate faster than codon 13 mutants during SDS-PAGE (Der et al, 1986; Murphy et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

“…The TN 61R mouse model is homozygous for Tyr-CRE-ER(T2) (Bosenberg et al, 2006) and LSL-Nras 61R (Burd et al, 2014) and was backcrossed seven generations to C57BL/6J mice. All other TN models were created using CRISPR-Cas9 to modify the endogenous LSL-Nras allele in TN 61R mice as described (Murphy et al, 2022). CRISPR-modified mice were backcrossed two generations to the founding TN 61R line to minimize off-target events.…”

Section: Methodsmentioning

confidence: 99%

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The OSUMMER lines: a series of ultraviolet-accelerated NRAS-mutant mouse melanoma cell lines syngeneic to C57BL/6

Murphy

Jensen

Arnold

et al. 2022

Preprint

Self Cite

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An increasing number of cancer subtypes are treated with front-line immunotherapy. However, approaches to overcome primary and acquired resistance remain limited. Pre-clinical mouse models are often used to investigate resistance mechanisms, novel drug combinations, and delivery methods; yet most of these models lack the genetic diversity and mutational patterns observed in human tumors. Here we describe a series of thirteen C57BL/6J melanoma cell lines to address this gap in the field. The Ohio State University-Moffitt Melanoma Exposed to Radiation (OSUMMER) cell lines are derived from mice expressing endogenous, melanocyte-specific, and clinically relevant Nras driver mutations (Q61R, Q61K, or Q61L). Exposure of these animals to a single, non-burning dose of ultraviolet B accelerates the onset of spontaneous melanomas with mutational patterns akin to human disease. Furthermore, in vivo irradiation selects against potent tumor antigens, which could prevent the outgrowth of syngeneic cell transfers. Each OSUMMER cell line possesses distinct in vitro growth properties, trametinib sensitivity, mutational signatures, and predicted antigenicity. Analysis of OSUMMER allografts shows a correlation between strong, predicted antigenicity and poor tumor outgrowth. These data suggest that the OSUMMER lines will be a valuable tool for modeling the heterogeneous responses of human melanomas to targeted and immune-based therapies.

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Prediction of probability distributions of molecular properties: towards more efficient virtual screening and better understanding of compound representations

Duda

Podlewska

2022

Mol Divers

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Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation

Cited by 16 publications

References 71 publications

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis

The OSUMMER lines: a series of ultraviolet-accelerated NRAS-mutant mouse melanoma cell lines syngeneic to C57BL/6

Prediction of probability distributions of molecular properties: towards more efficient virtual screening and better understanding of compound representations

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