Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology.
The immune system eliminates infected or transformed cells through the activation of the death receptor CD95. CD95 engagement drives the recruitment of the adaptor protein Fasassociated death domain protein (FADD), which in turn aggregates and activates initiator caspases-8 and -10. The CD95-mediated apoptotic signal relies on the capacity to form the CD95/FADD/caspases complex termed the death-inducing signalling complex (DISC). Cells are classified according to the magnitude of DISC formation as either type I (efficient DISC formation) or type II (inefficient). CD95 localised to lipid rafts in type I cells, whereas the death receptor was excluded from these domains in type II cells. Here, we show that inhibition of both PI3K class IA and serine-threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal. Strikingly, these molecular events took place independently of CD95L and the actin cytoskeleton. Overall, these findings highlight that the oncogenic PI3K/Akt signalling pathway participates in maintaining cells in a type II phenotype by excluding CD95 from lipid rafts. 2368 IntroductionThe death receptor CD95 (Fas/APO1) belongs to the tumour necrosis factor (TNF) receptor family. Although CD95 is ubiquitously expressed, its cognate ligand, CD95L, displays a more restricted expression pattern. This apoptotic ligand is found at the plasma membrane of immune cells [1] and participates in the elimination of transformed and infected cells. A common feature of the death receptors is the presence of an intracellular domain termed the death domain (DD). Binding of CD95L to CD95 triggers the recruitment at the DD level of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates proteases called caspase-8 and -10. The close vicinity of these caspases facilitates their activation and the induction of the caspase cascade, culminating in the death of the cell. The CD95/FADD/caspase-8 complex is called the death-inducing signalling complex (DISC) [2]. Investigations of the molecular mechanisms modulating the initial steps of CD95 signalling showed that the redistribution of CD95 into nanometer to micrometer-sized domains of the plasma membrane, termed lipid rafts, enhanced the formation of the DISC and the transmission of the apoptotic signal [3][4][5][6]. In addition, some anti-tumoral drugs eliminate malignant cells through the redistribution of CD95 into lipid rafts and the induction of a CD95L-independent apoptotic signal (e.g. rituximab [7], resveratrol [8,9], edelfosin [3,10] and cisplatin [11]).According to the signalling pathway triggered upon CD95 engagement, cells are classified, both in vivo and in vitro, as type I or type II cells [12]. In this regard, the DISC is efficiently formed in type I cells and the large amount of activated caspase-8 directly activates the executioner caspases-3, -6 and -7, which in turn process various intracellular substrates. On the contrary, type II cells displa...
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