Dataset Information

A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.

ABSTRACT: Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that ?-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that ?-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo. Unexpectedly, ?-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of ?-catenin in melanoma progression and therapy resistance. We further demonstrate that ?-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi.

SUBMITTER: Sinnberg T

PROVIDER: S-EPMC4919613 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.

Sinnberg Tobias T Makino Elena E Krueger Marcel A MA Velic Ana A Macek Boris B Rothbauer Ulrich U Groll Nicola N Pötz Oliver O Czemmel Stefan S Niessner Heike H Meier Friedegund F Ikenberg Kristian K Garbe Claus C Schittek Birgit B

EBioMedicine 20160501

Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause seco ...[more]

PMID: 27428425

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Project description:Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

Dataset Information

A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.

Publications

A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.

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