Featured
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Letter |
FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas
FBXO11 is identified as the F-box protein that normally targets BCL6 for degradation, and FBXO11 deletions or mutations that prevent this function and thus stabilize BCL6 are found in B-cell lymphomas.
- Shanshan Duan
- , Lukas Cermak
- & Michele Pagano
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Letter |
RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Although clinical trials have shown that RAF inhibitors prolong the survival of patients with BRAF-mutant melanoma, resistance inevitably develops; resistance is shown here to be frequently mediated by the expression of splicing variants of mutant BRAF.
- Poulikos I. Poulikakos
- , Yogindra Persaud
- & David B. Solit
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Letter |
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.
- Gideon Bollag
- , Peter Hirth
- & Keith Nolop
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Article |
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Cellular senescence — an irreversible cell-cycle arrest — has been implicated in suppressing tumour formation or growth. A new cellular signalling pathway that drives senescence has now been identified. This pathway does not involve most known mediators of senescence, and instead signals via the proteins Atf4, p27 and p21. Inactivating the proto-oncogene Skp2 in the context of oncogenic signalling can induce senescence through this new pathway, indicating that drugs that target Skp2 might be useful in cancer treatment.
- Hui-Kuan Lin
- , Zhenbang Chen
- & Pier Paolo Pandolfi
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Letter |
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.
- Poulikos I. Poulikakos
- , Chao Zhang
- & Neal Rosen
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Research Highlights |
Genetics: Protein's billion-year history
Mechanism for the activation of the anaplastic lymphoma kinase receptor