Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma

Krepler, Clemens; Xiao, Min; Samanta, Minu; Vultur, Adina; Chen, Hsin Yi; Brafford, Patricia; Reyes-Uribe, Patricia; Halloran, Molly B.; Chen, Thomas; He, Xijing; Hristova, Denitsa M.; Liu, Qin; Samatar, Ahmed A.; Davies, Michael A.; Nathanson, Katherine L.; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard; Villanueva, Jessie

doi:10.18632/oncotarget.12078

Cited by 21 publications

(14 citation statements)

References 43 publications

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“…Interestingly, a constitutively active construct NOTCH2‐NICD caused a higher increase in HEY1 expression than NOTCH1‐NICD in uveal melanoma cells . Alterations found in our study should be also considered in further research on melanoma cell response to drugs as both, Hippo and NOTCH pathways have been directly associated with resistance to inhibitors of the MAPK signaling pathway. A novel variant of FBXW7, V418M, that persists functional in melanoma cells, was identified in our study.…”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitindependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF V600E ) and RAS subtypes, including NRAS Q61R and the rare HRAS Q61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RAS Q61R cell lines harbored a MEK1 P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRAS Q61R /MEK P124S cells by trametinib, and this effect was also shown in HRAS Q61R / MEK P124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2 S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2 F1209V and NOTCH2 N2002S variants. Additionally, we found a novel FBXW7 V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas.

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Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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“…One of these microenvironmental signals could cause Notch activation. Furthermore, this model might also be of clinical relevance because the beneficial effect of combinatorial Notch and MAPK inhibition has previously been demonstrated in melanoma …”

Section: Discussionmentioning

confidence: 99%

JAG2 signaling induces differentiation of CD14+ monocytes into Langerhans cell histiocytosis-like cells

Schwentner

Jug

Kauer

et al. 2018

Journal of Leukocyte Biology

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Langerhans cell histiocytosis (LCH) is a MAPK pathway-driven disease characterized by the accumulation of CD1a + langerin + cells of unknown origin. We have previously reported that the Notch signaling pathway is active in LCH lesions and that the Notch ligand Jagged2 (JAG2) induces CD1a and langerin expression in monocytes in vitro. Here we show that Notch signaling induces monocytes to acquire an LCH gene signature and that Notch inhibition suppresses the LCH phenotype.In contrast, while also CD1c + dendritic cells or IL-4-stimulated CD14 + monocytes acquire CD1a and langerin positivity in culture, their gene expression profiles and surface phenotypes are more different from primary LCH cells. We propose a model where CD14 + monocytes serve as LCH cell precursor and JAG2-mediated activation of the Notch signaling pathway initiates a differentiation of monocytes toward LCH cells in selected niches and thereby contributes to LCH pathogenesis. K E Y W O R D SBRAFV600E, notch pathway, pediatric neoplasm BRAFV600E mutation alone is not instructive for a cell to develop an LCH phenotype.We have previously shown that the Notch pathway is active in LCH and that stimulation of the Notch pathway in the presence of

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“…Notch signaling has also been reported to contribute to resistance of melanoma cells to MAPK inhibitors (Krepler et al, ; Martz et al, ). Our data, on the contrary, show that downregulation of NOTCH1 is associated with resistance of BRAFV600E melanoma cells to MAPKi and forced expression of active Notch, NICD1, induces cell death preferentially in MAPKi‐resistant, but not MAPKi‐sensitive, BRAFV600E melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…In long‐term cultures, Notch signaling inhibition was shown to prolong the sensitivity of melanoma cells to BRAFi (Zhu et al, ). Furthermore, in BRAFV600E mutant melanoma with PTEN loss, targeting Notch signaling enhances the efficacy of ERKi (Krepler et al, ). Therefore, in BRAFV600E melanoma, Notch signaling seems to play a role in the context of their dependence on MAPK signaling.…”

Section: Introductionmentioning

confidence: 99%

Notch signaling activation induces cell death in MAPKi‐resistant melanoma cells

Mikheil

Prabhakar

Arshad

et al. 2019

Pigment Cell Melanoma Res

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The role of Notch signaling in melanoma drug resistance is not well understood. In this study, we show that although NOTCH proteins are upregulated in metastatic melanoma cell lines, Notch signaling inhibition had no effect on cell survival, growth, migration or the sensitivity of BRAFV600E‐melanoma cells to MAPK inhibition (MAPKi). We found that NOTCH1 is downregulated in melanoma cell lines with intrinsic and acquired resistance to MAPKi. Forced expression of NICD1, the active form of Notch1, caused apoptosis of the NOTCHlo, MAPKi‐resistant cells, but not the NOTCHhi, MAPKi‐sensitive melanoma cell lines. Whole transcriptome‐sequencing analyses of NICD1‐transduced MAPKi‐sensitive and MAPKi‐resistant cells revealed differential regulation of endothelin 1 (EDN1) by NICD1, that is, downregulation in MAPKi‐resistant cells and upregulation in MAPKi‐sensitive cells. Knockdown of EDN1 partially mimicked the effect of NICD1 on the survival of MAPKi‐resistant cells. We show that the opposite regulation of EDN1 by Notch signaling is mediated by the differential regulation of c‐JUN by NICD1. Our data show that MAPKi‐resistant melanoma cells acquire vulnerability to Notch signaling activation and suggest that Notch‐c‐JUN‐EDN1 axis is a potential therapeutic target in MAPKi‐resistant melanoma.

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Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma

Cited by 21 publications

References 43 publications

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

JAG2 signaling induces differentiation of CD14+ monocytes into Langerhans cell histiocytosis-like cells

Notch signaling activation induces cell death in MAPKi‐resistant melanoma cells

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