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Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X L , which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer. Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2–like 1 (BCL-X L ), which has shown clinical efficacy in some BCL-2–dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X L inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers.

The kinase PI(3)Kδ is shown to be required for the immunosuppressive function of regulatory T cells; inactivation of PI(3)Kδ in these cells leads to enhanced cytotoxic T-cell function and restricts tumour growth and metastasis in a variety of mouse tumour models. p110δ inhibitors limit T reg activity This paper shows that the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) is critically required for the immunosuppressive function of regulatory T (T reg ) cells. Inactivation of p110δ in T reg cells leads to enhanced cytotoxic T-cell function and restricts tumour growth and metastasis in a variety of mouse tumour models. This finding identifies p110δ as a druggable kinase target for which inhibition boosts the cancer-suppressive potential of the immune system. Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias 1 , 2 . As p110δ is primarily expressed in leukocytes 3 , drugs against p110δ have not been considered for the treatment of solid tumours 4 . Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8 + cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics 1 . Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas 1 . These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms 2 . The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear 2 . Here we show that the pro-survival protein MCL1 (ref. 3 ) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7 , conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.

Nature 510, 407–411 (2014); doi:10.1038/nature13444 Queen Mary University London notified Nature and University College London that there is reason to question the provenance of the data for Fig. 5b, d, e of this Letter (Fig. 5a, c data are unaffected). Ongoing studies are investigating the reportedeffect of p110δ inhibition in the pancreatic cancer mouse model.

Inhibitors against the p110δisoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8^sup +^ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.