Human tumor genomics and zebrafish modeling identify
            <i>SPRED1</i>
            loss as a driver of mucosal melanoma

Ablain, Julien; Xu, Mengshu; Rothschild, Harriet; Jordan, Richard C.; Mito, Jeffrey K.; Daniels, Brianne H.; Bell, Caitlin; Joseph, Nancy M.; Wu, Hong Gyun; Bastian, Boris C.; Zon, Leonard I.; Yeh, Iwei

doi:10.1126/science.aau6509

Cited by 123 publications

(158 citation statements)

References 65 publications

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“…The inhibition of the ERK pathway can even worsen the tumorigenesis of melanoma under certain conditions. Recently, biallelic inactivation mutations of Spred1 have been reported in patients with mucosal melanoma …”

Section: Roles Of Sprouty/spred During Tumorigenesis and Metastasismentioning

confidence: 99%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.

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Section: Roles Of Sprouty/spred During Tumorigenesis and Metastasismentioning

confidence: 99%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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“…Several studies have utilized array-based comparative genomic hybridization or whole-exome sequencing (WES) and targeted sequencing to investigate the mutational spectra of MM (15)(16)(17)(18). Furney and colleagues (2013) conducted the first whole-genome sequencing (WGS) analysis of 5 MM samples (16).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations

Zhou

Shi

Tao

et al. 2019

Clinical Cancer Research

140

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Purpose: Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications. Experimental Design: Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR-based validation study of an independent MM cohort (n ¼ 80). Guided by these molecular insights, the FDA-approved CDK4/6 inhibitor palbociclib was tested in an MM patient-derived xenograft (PDX) trial. Results: Besides the identification of well-recognized driver mutations of BRAF (3.1%), RAS family (6.2%), NF1 (7.8%), and KIT (23.1%) in MMs, our study also found that (i) mutations and amplifications in the transmembrane nucleoporin gene POM121 (30.8%) defined a patient subgroup with higher tumor proliferation rates; (ii) enrichment of structural variations between chromosomes 5 and 12 defined a patient subgroup with significantly worse clinical outcomes; (iii) over 50% of the MM patients harbored recurrent focal amplification of several oncogenes (CDK4, MDM2, and AGAP2) at 12q13-15, and this co-occurred significantly with amplification of TERT at 5p15, which was verified in the validation cohort; (iv) the PDX trial demonstrated robust antitumor effects of palbociclib in MMs harboring CDK4 amplification. Conclusions: Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments.

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“…Alterations in RAS and RAF isoforms account for the most common mutations in MAPK signaling (Ablain et al, ; Shain et al, ). RAS exhibits a defined threshold of activity required for either homeostasis or for malignant transformation.…”

Section: Mapk Signalingmentioning

confidence: 99%

“…Activation of MEK (via phosphorylation) is induced by RAF isoforms, and its downstream target is ERK (Lu et al, ; Hazar‐Rethinam et al, ). Trametinib (Ablain et al, ), selumetinib (Ruess et al, ), and SL‐327 (Yan et al, ) are MEK inhibitors. Sensitivity to MEK inhibitors often occurs when there are mutations in upstream kinases.…”

Section: Mapk Signalingmentioning

confidence: 99%

“…Loss of SPRED1 and increase of the activity for sterol regulator element binding protein 1 (SREBP‐1) are contributed to drug resistance in melanoma. SPRED1 is a negative regulator of MAPK, so loss of SPRED1 causes MAPK activation and cancer proliferative features (Ablain et al, ). About 80% of melanoma patients develop resistance to BRAF blockade therapy.…”

Section: Mapk In Cancer Growth and Drug Resistancementioning

confidence: 99%

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Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

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Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

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Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma

Cited by 123 publications

References 65 publications

The Sprouty/Spred family as tumor suppressors: Coming of age

The Sprouty/Spred family as tumor suppressors: Coming of age

Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

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