Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells

Misek, Sean A.; Appleton, Kate M; Dexheimer, Thomas S.; Lisabeth, Erika M.; Lo, Roger S.; Larsen, Scott D.; Gallo, Kathleen A.; Neubig, Richard R.

doi:10.1038/s41388-019-1074-1

Cited by 40 publications

(97 citation statements)

References 78 publications

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“…Furthermore, by proteomic analysis, we demonstrated that DDR2 depletion with siRNA, DDR2 selective inhibition or Dasatinib treatment induce a decrease of RhoA signaling. Thoese results confirmed the recent study of Misek et al, which showed that in resistant cells there is an accumulation of actin stress fiber due to RhoA activation (Misek et al 2019).…”

Section: Discussionsupporting

confidence: 90%

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

Sala

Allain

Jabouille

et al. 2019

Preprint

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Anti-BRAF plus an anti-MEK is currently used in first line for the management of patients presenting metastatic melanomas harboring the BRAF V600E mutation. However, the main issue during targeted therapy is the acquisition of cellular resistance in 80% of the patients, which is associated with an increased metastasis due to the hyperactivation of MAP kinase pathway. Previous reports have indicated that Discoidin Domain Receptors (DDRs) 1 and 2 can activate this pathway. To study the role of DDRs in melanoma cell resistance to targeted therapy, we first determined that DDRs are overexpressed in vemurafenib resistant cells compared to sensitive cells. We demonstrated that DDRs depletion or inactivation by DDRs inhibitors such as dasatinib or CR-13542 reduces tumor cell proliferation, due to a decrease of MAP kinase pathway activity in resistant cells. Finally, we confirmed these results in vivo in a xenograft mouse model and show that DDRs could be new therapeutic targets in resistant patients with metastatic melanoma. We propose that dasatinib could be a second-line treatment after the bi-therapy in resistant patients overexpressing DDRs.

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Section: Discussionsupporting

confidence: 90%

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

Sala

Allain

Jabouille

et al. 2019

Preprint

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“…Cell lines, reagents, and antibodies: Parental (denoted by a P suffix in the cell line name) and matched isogenic BRAFiresistant cells (denoted by an R suffix in the cell line name) were either a gift (M229P/R, M238P/R) from Dr. Roger Lo (UCLA) or generated in our laboratory (UACC62P/R). These cells were generated and cultured as described below (47).…”

Section: Methodsmentioning

confidence: 99%

“…M229P/R and M238P/R RNA-Seq data was downloaded from GSE75313 (16). UACC62P/R RNA-Seq data was previously generated by our group and was deposited under GSE115938 (47). The PRISM drug response dataset was downloaded from the DepMap data download portal (depmap.org/portal/download).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…YAP1 has been previously implicated in BRAFi resistance (4,(44)(45)(46)(47), so it is critical to understand whether ibrutinib is altering YAP1 activity. Transcriptionally inactive YAP1 is sequestered in the cytosol and upon various stimuli YAP1 can translocate into the nucleus where it modulates gene transcription.…”

Section: Ibrutinib Reduces the Nuclear Accumulation Of Yap1mentioning

confidence: 99%

“…Some phosphorylation events on YAP1 by LATS1/2 lead to inactivation and subsequent proteasomal degradation (42) whereas phosphorylation at other sites, targeted by YES1 and other kinases, is critical for YAP1 nuclear translocation and activation (43). YAP1 is activated in BRAFi-resistant melanoma cells and silencing or deletion of YAP1 reverses BRAFi resistance (4,(44)(45)(46)(47). In addition to melanoma, YAP1 has been implicated in many other cancer types including breast cancer (48), glioblastoma (49), pancreatic cancer (50), hepatocellular…”

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Ibrutinib blocks YAP1 activation and reverses BRAFi resistance in melanoma cells

Misek

Newbury

Chekalin

et al. 2020

Preprint

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Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, another BTK inhibitor with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched in YAP1 target genes and we showed that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.

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A B‐Raf V600E gene signature for melanoma predicts prognosis and reveals sensitivity to targeted therapies

2022

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Background B‐Raf V600E mutations account for about half of all skin cutaneous melanoma cases, and patients with this mutation are sensitive to BRAF inhibitors. However, aberrations in other genes in the MAPK/ERK pathway may cascade a similar effect as B‐Raf V600E mutations, rendering those patients sensitive to BRAF inhibitors. We rationalized that defining a signature based on B‐Raf pathway activity may be more informative for prognosis and drug sensitivity prediction than a binary indicator such as mutation status. Methods In this study, we defined a B‐Raf signature score using RNA‐seq data from TCGA. A higher score is shown to not only predict B‐Raf mutation status, but also predict other aberrations that could similarly activate the MAPK/ERK pathway, such as B‐Raf amplification, RAS mutation, and EGFR amplification. Results We showed that patients dichotomized by the median B‐Raf score is more significantly stratified than by other metrics of measuring B‐Raf aberration, such as mutation status, gene expression, and protein expression. We also demonstrated that high B‐Raf score predicts higher sensitivity to B‐Raf inhibitors SB590885 and PLX4720, as expected, but also correlated with sensitivity to drugs targeting other relevant oncogenic pathways. Conclusion The BRAF signature may better help guide targeted therapy for melanoma, and such a framework can be applied to other cancers and mutations to provide more information than mutation status alone.

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Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells

Cited by 40 publications

References 78 publications

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching

Ibrutinib blocks YAP1 activation and reverses BRAFi resistance in melanoma cells

A B‐Raf V600E gene signature for melanoma predicts prognosis and reveals sensitivity to targeted therapies

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