Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho

Behera, Reeti; Kaur, Amanpreet; Webster, Marie R.; Kim, Su Yeon; Ndoye, Abibatou; Kugel, Curtis H.; Alicea, Gretchen M.; Wang, Joshua; Ghosh, Kanad; Cheng, Phil F.; Lisanti, Sofia; Marchbank, Katie; Dang, Vanessa; Levesque, Mitchell P.; Dummer, Reinhard; Xu, Xiaowei; Herlyn, Meenhard; Aplin, Andrew E.; Roesch, Alexander; Caino, M. Cecilia; Altieri, Dario C.; Weeraratna, Ashani T.

doi:10.1158/1078-0432.ccr-17-0201

Cited by 32 publications

(28 citation statements)

References 29 publications

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“…We therefore reasoned that BETi/MEKi could be a strategy to overcome resistance to targeted‐ and immune‐therapy. We first tested the efficacy of combining BET and MEK inhibitors in a BRAFi‐resistant Yumm1.7‐BR syngeneic mouse model with a fully competent immune system (Behera et al , ). The combination of OTX‐015 and PD901 inhibited tumor growth rate and increased animal survival (Fig A and B, ).…”

Section: Resultsmentioning

confidence: 99%

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Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

et al. 2018

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Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS‐mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS‐mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co‐targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment‐resistant tumor types.

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Section: Resultsmentioning

confidence: 99%

“…YUMM1.7‐BRAFi‐R cells were derived from the BRAFV600E‐PTEN L/L mouse model (Dankort et al, ) and established as described (Meeth et al , ; Behera et al , ). Yumm1.7‐BRAFi‐R cells (2.5 × 10 5 ) were suspended in Matrigel and injected subcutaneously into C57Bl/6 mice (Charles River).…”

Section: Methodsmentioning

confidence: 99%

Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

et al. 2018

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“…One of the identified suppressive mechanisms shows that the PPARγ pathway modulates the transition between epithelial and mesenchymal phenotypes of cancer cells. PPARγ activation induces reverse epithelial-mesenchymal transition, also termed MET, by directly increasing the expression of E-cadherin (39,40) and indirectly inhibiting the canonical WNT/β-catenin pathway (41)(42)(43). Consequently, cancer cells exhibit decreased invasion and migration, blocking the spreading of metastatic cells from the primary tumor to secondary metastatic organs.…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

et al. 2019

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Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is signifi cantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists signifi cantly reduces brain metastatic burden in vivo. Our study clarifi es a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.

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“…After acclimation for 1 wk, weight-matched mice were randomized into 4 groups (n = 8/group) and treated s.c. with 1.5 mg/(kg/d) Tac (Prograft; Astellas Pharma, Tokyo, Japan) or 10 ml/(kg/d) vehicle (Vh; olive oil; MilliporeSigma, Billerica, MA, USA), with or without recombinant mouse Klotho (rKlotho; 10 mg/kg), once every 2 d by intraperitoneal injection for 4 wk. rKlotho protein, which contains the entire extracellular region (Ala35-Lys982), without the transmembrane domain and intracellular domain, was purchased from R&D Systems (Minneapolis, MN, USA), and its biologic activity has been extensively characterized by the manufacturer and in previous reports (11,(16)(17)(18)(19)(20)(21). Administration routes and drug doses were selected based on previous studies that showed a significant renal protective effect in a Tac-induced mouse model of renal injury (11).…”

Section: Tac-induced Renal Injury Mouse Modelmentioning

confidence: 99%

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

et al. 2018

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Recently, we showed that tacrolimus‐induced renal injury was closely associated with impairment of autophagy clearance, and Klotho deficiency aggravated tacrolimus‐induced renal injury. In this study, we evaluated the effect of Klotho treatment on autophagy clearance in tacrolimus‐induced renal injury. We evaluated the effect of Klotho on tacrolimus‐induced renal injury in an experimental mouse model and in vitro by treatment with tacrolimus and/or recombinant mouse Klotho. In vivo and in vitro studies showed that tacrolimus treatment impaired lysosomal acidification and decreased cathepsin B activity, expression of lysosome‐associated membrane protein 2, and expression of transcription factor EB (TFEB), a master regulator for lysosomal biogenesis. These results were improved by Klotho treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effect of Klotho, indicating that the protective effect of Klotho was closely associated with lysosome function. Klotho induced nuclear translocation of TFEB through inhibition of phosphorylation of glycogen synthase kinase 3β (GSK3β) by confirming using CHIR99021, a GSK3β inhibitor. Collectively, our data suggest that Klotho improves autophagy clearance via activation of lysosomal function in tacrolimus‐induced nephrotoxicity.—Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury. FASEB J. 33, 2694–2706 (2019). http://www.fasebj.org

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Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho

Cited by 32 publications

References 29 publications

Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

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