ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma

Ojha, Rani; Leli, Nektaria Maria; Onorati, Angelique; Piao, Shengfu; Verginadis, Ioannis I.; Tameire, Feven; Rebecca, Vito W.; Chude, Cynthia I.; Murugan, Sengottuvelan; Fennelly, Colin; Noguera-Ortega, Estela; Chu, Charleen T.; Liu, Shujing; Xu, Xiaowei; Krepler, Clemens; Xiao, Min; Xu, Wei; Wei, Zhi; Frederick, Dennie T.; Boland, Genevieve M.; Mitchell, Tara C.; Karakousis, Giorgos C.; Schuchter, Lynn M.; Flaherty, Keith T.; Zhang, Gao; Herlyn, Meenhard; Koumenis, Constantinos; Amaravadi, Ravi K.

doi:10.1158/2159-8290.cd-18-0348

Cited by 77 publications

(87 citation statements)

References 46 publications

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“…However, resistance to BRAF inhibitions limited the onset time, which restricted the duration of effective treatment . Mechanisms of resistance were fasten on MAPK (mitogen‐activated protein kinase) pathway reactivation, gene expression change including acquired overexpression of upstream NRSA and MEK mutations, amplification or alternate splicing of mutant BRAF, reactivation and autophagy of ERK (extracellular regulated protein kinases), COT and MLKs overexpression . Besides, tumor microenvironment change such as microRNA and aryl hydrocarbon receptor (AhR) transcription factor has been found in BRAF resistance .…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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Background Melanoma is a potentially fatal malignancy with poor prognosis. Several recent studies have demonstrated that combination therapy of BRAF and MEK inhibition achieved better curative effect and appeared less toxic effects. We conducted a meta‐analysis to evaluate the efficacy and safety between BRAF inhibition plus MEK inhibition combination therapy and BRAF inhibition monotherapy in melanoma patients. Methods We performed the search in PubMed, EMBASE, and the Cochrane Library from January 2010 to January 2019. Inclusion and exclusion of studies, assessment of quality, outcome measures, data extraction, and synthesis were independently accomplished by two reviewers. Revman 5.3 software was used for the meta‐analysis. Results Totally, seven randomized controlled trials involving 3146 patients met our inclusion criteria. Comparing the results of combination therapy and monotherapy, combination therapy significantly improved OS (RR = 1.13; 95% CI, 1.08, 1.19; P < 0.00001), ORR (RR = 1.36; 95% CI, 1.28, 1.45; P < 0.00001), PFS (RR = 0.57; 95% CI, 0.52, 0.63; P < 0.00001) and reduced deaths (RR = 0.78; 95% CI, 0.69, 0.88; P < 0.0001). Skin‐related adverse events such as hyperkeratosis, cutaneous squamous‐cell carcinoma were less compared with monotherapy. However, gastrointestinal events like nausea, diarrhea, and vomiting were at a higher frequency. Conclusion Doublet BRAF and MEK inhibition achieved better survival outcomes over single‐agent BRAF inhibition and occurred less skin‐related events, but gastrointestinal events were more in combination therapy.

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Section: Discussionmentioning

confidence: 99%

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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“…Thus, the canonical and noncanonical ER stress response programs link autophagy and ER Cancer Research. reactivation as a unified pathway of resistance to MAPK inhibitors (80).…”

Section: The Er Stress Response/targeted Therapiesmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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“…Although mutation of some genes, such as BRAF, NRAS, and TP53, have been identified as risk factors for melanoma progression (Byron et al, 2012;Posch et al, 2013;Lissanu Deribe et al, 2016;Hayward et al, 2017;Ojha et al, 2019), our knowledge of molecular mechanism underlying the malignant melanoma remains obscure. Recently, numerous lncRNAs have been discovered in diverse types of tumors through high-throughput RNA sequencing technologies.…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA LINC-PINT Suppresses Cell Proliferation and Migration of Melanoma via Recruiting EZH2

Wang

et al. 2019

Front. Cell Dev. Biol.

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Long non-coding RNAs (lncRNAs) have been identified as crucial regulators in many human cancers. Many lncRNAs show aberrant expression in cancer, and some of them play critical roles in tumor proliferation, invasion, and metastasis. However, the regulatory functions of lncRNAs in melanoma progression remain to be elucidated. We utilized the Real-time PCR methodology to determine the expression of LINC-PINT in melanoma cell lines. To evaluate the effect of LINC-PINT on tumorigenesis of melanoma, we used Cell Counting Kit-8 (CCK8) and colony formation assay. Flow cytometry assay was used to detect the function of LINC-PINT on cell cycle status. PINT-interacting proteins were identified by chromatin isolation using RNA purification (ChIRP). Microarray assay and bioinformatics analysis were used to find the potential target genes of LINC-PINT and the status of LINC-PINT target gene candidate was verified using chromatin immunoprecipitation assay (ChIP). LINC-PINT plays a role in suppressing the tumorigenicity of melanoma, which was further determined by xenograft model assay. LINC-PINT was significantly downregulated in melanoma tissues and cell lines. The overexpression of LINC-PINT in tumor cells resulted in significant tumor growth reduction and migration inhibition in A375, Mum2B and CRMM1 cells. Results based on the in vivo xenograft model were further consistent with the in vitro findings that LINC-PINT impeded growth and metastasis of melanoma cells. Microarray assay and bioinformatics analysis indicated that CDK1, CCNA2, AURKA, and PCNA were potential targets of LINC-PINT. In conclusion, LINC-PINT inhibits the tumorigenicity of melanoma through recruiting EZH2 to the promoter of its target genes, leading to H3K27 trimethylation and epigenetic silencing of target genes. LINC-PINT may serve as a novel diagnostic and therapeutic target for melanoma.

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ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma

Cited by 77 publications

References 46 publications

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Long Non-coding RNA LINC-PINT Suppresses Cell Proliferation and Migration of Melanoma via Recruiting EZH2

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