A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo

Lister, James; Capper, Amy; Zeng, Zhiqiang; Mathers, Marie E.; Richardson, Jennifer; Paranthaman, Karthika; Jackson, Ian J.; Patton, E. Elizabeth

doi:10.1038/jid.2013.293

Cited by 91 publications

(84 citation statements)

References 37 publications

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“…Moreover, we found eight candidate loci conferring resistance to PLX4720 treatment. Interestingly, both lists contained Mitf, which is a well-known melanoma oncogene amplified in ∼10% of primary and ∼20% of metastatic melanomas (35,52,53) and has been described as a mediator of drug resistance in melanoma (35-37, 54, 55).…”

Section: Discussionmentioning

confidence: 99%

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

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

129

127

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BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAF V600 -mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf V618E (analogous to the human BRAF V600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf V618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes. melanoma | drug resistance | BRAF inhibitors | mouse models T he discovery that ∼50-60% of melanomas carry BRAF V600E point mutations (1) prompted the generation of compounds specifically targeting this hyperactive mutated kinase. One such compound, PLX4032, has shown unprecedented therapeutic efficacy in clinical trials and was therefore FDA-approved for clinical therapy under the name vemurafenib. Despite its remarkable efficacy, almost all patients receiving BRAF inhibitor treatment relapsed after weeks to months of therapy (2-5). Acquired resistance to BRAF inhibitors has since been a major focus of research and two major paths to resistance have emerged: MAPK-dependent and MAPK-independent mechanisms. MAPK-dependent mechanisms primarily involve reactivation of the MAPK pathway to substitute for the inhibition of BRAF V600E. This may be achieved through mechanisms including expression of alternative splicing forms of BRAF V600E

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Section: Discussionmentioning

confidence: 99%

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Perna

Karreth

Rust

et al. 2015

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

129

127

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“…42,43 Other factors that can induce melanoma regression include decreased microphthalmia transcription factor activity within melanocytes. 44 Another mechanism, proposed by Bastian,45 suggests that decreased telomerase activity can lead to abnormal telomere function, and thus induce replicative senescence in melanoma cells, resulting in the generation of apoptotic bodies and a T lymphocyte response.…”

Section: Spontaneous Regression In Melanomamentioning

confidence: 99%

Regression in primary cutaneous melanoma: etiopathogenesis and clinical significance

Aung

Nagarajan

Prieto

2017

Laboratory Investigation

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Though not required currently for staging, regression is a histopathologic parameter typically reported upon diagnosis of an invasive primary cutaneous melanoma. The studies examining the prognostic significance of regression in patient outcome have yielded controversial findings; likely because the definition and assessment of regression have not been consistent, in addition to subjectivity of pathologists' interpretation. Regression is histologically characterized by variable decrease in the number of melanoma cells accompanied by the presence of a host response consisting of dermal fibrosis, inflammatory infiltrate, melanophages, ectatic blood vessels, epidermal attenuation, and/or apoptosis of keratinocytes or melanocytes; the relative extent of these features depends on the stage of the regression. However, the magnitudes to which these individual changes must be present to meet the threshold of histologic regression have not been well defined or agreed upon, and thus, the definition and classification of histologic regression in melanoma varies considerably among institutions and even among individual pathologists. In order to determine the clinical significance of histologic analysis of regression, there is a compelling need for a universal scheme to objectively define and assess histologic regression in primary cutaneous melanoma, so that the biologic and prognostic significance of this process may be completely understood.

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“…Utilizing this mitfa temperature sensitive allele, we found that lowered levels of MITF activity cooperated with BRAF V600E mutations to promote nevi and melanoma in vivo, and that loss of MITF in established melanomas led to rapid melanoma regression ( Fig. 2A and B) (20). Furthermore, while melanoma incidence was similar in BRAF V600E p53 and BRAF V600E mitf fish, the histopathology of the melanomas were strikingly different.…”

Section: Mitf Is Mutated and Amplified In Melanoma And Is A Melanomamentioning

confidence: 91%

“…2C and D). An important implication from this animal model is the validation of MITF as a drug target in melanoma, but also that caution would be needed in this approach, because insufficient targeting of MITF activity (leading to simply a reduction in MITF activity) could be oncogenic (20).…”

Section: Mitf Is Mutated and Amplified In Melanoma And Is A Melanomamentioning

confidence: 99%

Zebrafish as a model system to investigate the function of MITF in melanoma

Capper¹,

Patton²

2014

AACR Education book

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A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo

Cited by 91 publications

References 37 publications

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model

Regression in primary cutaneous melanoma: etiopathogenesis and clinical significance

Zebrafish as a model system to investigate the function of MITF in melanoma

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