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

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

doi:10.1101/381806

Cited by 3 publications

(3 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have reported that alterations of RHOA mediate tumor invasion and drug resistance in cancer. Misek et al 18 . found that RHOA contributes to BRAF inhibitor resistance in Sox9High/Sox10Low melanoma cells by regulating activation of the RhoA family signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have reported that alterations of RHOA mediate tumor invasion and drug resistance in cancer. Misek et al 18 found that RHOA contributes to BRAF inhibitor resistance in Sox9High/Sox10Low melanoma cells by regulating activation of the RhoA family signaling pathway. In addition, partner genes with high degrees in the SL network, such as NAE1 and TP53, also played an important role in the development and progression of cancer.…”

Section: Drug-response-related Genetic Interaction Network Shows Biological Characteristicsmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Interaction-Based Biomarkers Identification for Drug Resistance and Sensitivity in Cancer Cells

Han

Wang

Dong

et al. 2019

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Cancer cells generally harbor hundreds of alterations in the cancer genomes and act as crucial factors in the development and progression of cancer. Gene alterations in the cancer genome form genetic interactions, which affect the response of patients to drugs. We developed an algorithm that mines copy number alteration and whole-exome mutation profiles from The Cancer Genome Atlas (TCGA), as well as functional screen data generated to identify potential genetic interactions for specific cancer types. As a result, 4,529 synthetic viability (SV) interactions and 10,637 synthetic lethality (SL) interactions were detected. The pharmacogenomic datasets revealed that SV interactions induced drug resistance in cancer cells and that SL interactions mediated drug sensitivity in cancer cells. Deletions of HDAC1 and DVL1 , both of which participate in the Notch signaling pathway, had an SV effect in cancer cells, and deletion of DVL1 induced resistance to HDAC1 inhibitors in cancer cells. In addition, patients with low expression of both HDAC1 and DVL1 had poor prognosis. Finally, by integrating current reported genetic interactions from other studies, the Cancer Genetic Interaction database (CGIdb) ( http://www.medsysbio.org/CGIdb ) was constructed, providing a convenient retrieval for genetic interactions in cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Drug-response-related Genetic Interaction Network Shows Biological Characteristicsmentioning

confidence: 99%

Genetic Interaction-Based Biomarkers Identification for Drug Resistance and Sensitivity in Cancer Cells

Han

Wang

Dong

et al. 2019

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

show abstract

“…Our recent findings indicated a role of the Rho/MRTF pathway in migration, invasion and metastasis of aggressive human cutaneous melanoma (20,34), as well as in the acquired resistance of BRAF mutant melanoma cells to BRAF inhibitors (34). Therefore, we hypothesized that the Rho/MRTF pathway might play a role in the intrinsic resistance of some of the NRAS mutant melanoma cells to trametinib-induced inhibition of cell viability.…”

Section: Mrtf Pathway Activation Correlates With Trametinib Resistancementioning

confidence: 97%

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Appleton

Palsuledesai

Misek

et al. 2019

Preprint

View full text Add to dashboard Cite

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (~50% BRAF V600 mutations and ~30% NRAS mutations). While targeted therapies have yielded success in BRAF V600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

show abstract

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Dratkiewicz

Simiczyjew

Pietraszek-Gremplewicz

et al. 2019

IJMS

View full text Add to dashboard Cite

Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of inhibitors directed against EGFR (epidermal growth factor receptor) and MET (hepatocyte growth factor receptor) trigger a synergistic cytotoxic effect in human melanoma cells, and decrease their invasive abilities. In this study, we aimed to generate and characterize melanoma cells resistant to vemurafenib treatment, and then to evaluate the effectiveness of a previously developed therapy in this model. We showed that melanoma cells resistant to the BRAF inhibitor are characterized by a lower proliferation rate and they acquire a spindle-like shape. Using Western Blot, we also noticed increased levels of EGFR, MET, and selected markers of cancer stem cells in generated cell lines. Resistant cells also exhibited increased invasive abilities and elevated proteolytic activity, observed using scratch wound assays and gelatin zymography. Moreover, combination therapy reduced their viability, as measured with a colorimetric cytotoxicity test, and decreased invasiveness. The obtained results validate the application of combination therapy directed against EGFR and MET in melanoma cells resistant to treatment with inhibitors of mutated BRAF.

show abstract

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

Cited by 3 publications

References 56 publications

Genetic Interaction-Based Biomarkers Identification for Drug Resistance and Sensitivity in Cancer Cells

Genetic Interaction-Based Biomarkers Identification for Drug Resistance and Sensitivity in Cancer Cells

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

Contact Info

Product

Resources

About