ORCID Profile
0000-0002-3825-6381
Current Organisation
Public University of Navarra
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: The Company of Biologists
Date: 2014
DOI: 10.1242/JCS.146373
Abstract: The Target Of Rapamycin TOR kinase regulates cell growth and ision. Rapamycin only inhibits a subset of TOR activities. Here we show that in contrast to the mild impact of rapamycin on cell ision, blocking the catalytic site of TOR with the Torin1 inhibitor completely arrests growth without cell death in S.pombe. A mutation of the Tor2 TORC1 glycine residue (G2040D) that lies adjacent to the key Torin interacting tryptophan provides Torin1 resistance, confirming Torin1's specificity for TOR. Using this mutation we show that Torin1 advanced mitotic onset before inducing growth arrest. In contrast to TOR inhibition with Rapamycin, regulation by either Wee1 or Cdc25 was sufficient for this Torin1 induced advanced mitosis. Torin1 promoted a Polo and Cdr2 kinase controlled drop in Wee1 levels. Experiments in human cell lines re-capitulated these yeast observations mTOR was inhibited by Torin1, Wee1 levels declined and mitotic commitment was advanced in HeLa cells. Thus, the regulation of the mitotic inhibitor Wee1 by TOR signalling is a conserved mechanism that helps to couple cell cycle and growth controls.
Publisher: EMBO
Date: 12-06-2017
Abstract: Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF‐induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re‐activation in a paracrine manner. Most importantly, EDN1 not only supports MITF‐high populations through the endothelin receptor B (EDNRB), but also AXL‐high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL‐high‐expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL‐high cells.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2017
DOI: 10.1158/2159-8290.CD-16-0955
Abstract: Genomic ersity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy. Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient s les and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov 7(8) 832–51. ©2017 AACR. See related commentary by Jenkins and Barbie, p. 799. This article is highlighted in the In This Issue feature, p. 783
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Claudia Wellbrock.