Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent (original) (raw)
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Biochemical Journal, 2011
Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in...
The FASEB Journal, 2012
Class IA PI3K isoforms have divergent, nonredundant cell biological roles. In untransformed cells and tissues, p110␣ and p110 are ubiquitously expressed, whereas p110␦ expression is highly enriched in leukocytes. High levels of p110␦ expression have been documented in some solid tumor cell lines, but the functional role is unknown. This study aimed to elucidate the link between elevated expression of p110␦ PI3K and cancer. We report that in breast and prostate cancer cells that contain leukocyte levels of p110␦, p110␦ activity dampens the activity of the PTEN tumor suppressor. Indeed, inactivation of p110␦ in these cells led to PTEN activation, suppression of Akt phosphorylation, and inhibition of cell proliferation, with inhibition of PTEN activity being able to counterbalance p110␦ inactivation. Likewise, forced overexpression of p110␦ in cells with low p110␦ expression reduced PTEN activity, resulting in increased Akt phosphorylation. Our data indicate that the oncogenic potential of p110␦ PI3K overexpression might at least partially act through PTEN inactivation, and that p110␦-selective PI3K inhibitors can have a dual antitumor mechanism, namely by directly inhibiting p110␦ signaling and by a broader inhibition of class I PI3K activity through PTEN activation. These data may have important implications in the intervention of breast cancer.
Cancer Research, 2007
The signaling pathways involving class I phosphatidylinositol 3-kinases (PI3K) and the phosphatidylinositol-(3,4,5)-trisphosphate phosphatase PTEN regulate cell proliferation and survival. Thus, mutations in the corresponding genes are associated to a wide variety of human tumors. Heterologous expression of hyperactive forms of mammalian p110A and p110B in Saccharomyces cerevisiae leads to growth arrest, which is counterbalanced by coexpression of mammalian PTEN. Using this in vivo yeast-based system, we have done an extensive functional analysis of germ-line and somatic human PTEN mutations, as well as a directed mutational analysis of discrete PTEN functional domains. A distinctive penetrance of the PTEN rescue phenotype was observed depending on the levels of PTEN expression in yeast and on the combinations of the inactivating PTEN mutations and the activating p110A or p110B mutations analyzed, which may reflect pathologic differences found in tumors with distinct alterations at the p110 and PTEN genes or proteins. We also define the minimum length of the PTEN protein required for stability and function in vivo. In addition, a random mutagenesis screen on PTEN based on this system allowed both the reisolation of known clinically relevant PTEN mutants and the identification of novel PTEN loss-of-function mutations, which were validated in mammalian cells. Our results show that the PI3K/PTEN yeast-based system is a sensitive tool to test in vivo the pathologic properties and the functionality of mutations in the human p110 proto-oncogenes and the PTEN tumor suppressor and provide a framework for comprehensive functional studies of these tumor-related enzymes.
Biochemical Journal, 2012
The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/− mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P3, which is produced by the class I isoforms of PI3K (p110α, p110β, p110γ and p110δ). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110β, and that p110β, but not p110α, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110α can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110α- or p110β-selective inhibitors, we confirm that in...
Molecular Cancer Therapeutics, 2013
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with subnanomolar IC 50 s against PI3Ka and PI3Kd. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Ka compared with PI3Kb in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. Mol Cancer Ther; 12(11); 2319-30. Ó2013 AACR.
Mutated PI 3-Kinases: Cancer Targets on a Silver Platter
Cell Cycle, 2005
The PI3K signaling pathway is upregulated in numerous cancers. The catalytic subunit p110α of PI3K shows hot spot mutations in nearly 30% of several types of solid tumors. The most prominent of these mutations result in gain of enzymatic function, activate Akt signaling and induce oncogenic cellular transformation. The mutated p110α proteins are ideal targets for specific small molecule inhibitors that discriminate between the oncogenic and the wild-type forms of the enzyme. Such inhibitors could become highly effective anti-cancer drugs.
Molecular cancer therapeutics, 2015
Dysregulation of PI3K/ PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/ PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly-selective inhibitor of Class I PI3Ks (α,β,γ and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for Class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K and S6 phosphorylation in multiple tumor cell lines with diverse genetic alt...
The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models
Frontiers in Oncology, 2014
When PI3K (phosphatidylinositol-3 kinase) is activated by receptor tyrosine kinases, it phosphorylates PIP2 to generate PIP3 and activates the signaling pathway. Phosphatase and tensin homolog deleted on chromosome 10 dephosphorylates PIP3 to PIP2, and thus, negatively regulates the pathway. AKT (v-akt murine thymoma viral oncogene homolog; protein kinase B) is activated downstream of PIP3 and mediates physiological processes. Furthermore, substantial crosstalk exists with other signaling networks at all levels of the PI3K pathway. Because of its diverse array, gene mutations, and amplifications and also as a consequence of its central role in several signal transduction pathways, the PI3Kdependent axis is frequently activated in many tumors and is an attractive therapeutic target.The preclinical testing and analysis of these novel therapies requires appropriate and well-tailored systems. Mouse models in which this pathway has been genetically modified have been essential in understanding the role that this pathway plays in the tumorigenesis process. Here, we review cancer mouse models in which the PI3K/AKT pathway has been genetically modified.
Status of PI3K inhibition and biomarker development in cancer therapeutics
Annals of …, 2010
The phosphatidylinositol 3-kinase (PI3K) signalling pathway is integral to diverse cellular functions, including cellular proliferation, differentiation and survival. The 'phosphate and tensin homologue deleted from chromosome 10' (PTEN) tumor suppressor gene plays a critical role as a negative regulator of this pathway. An array of genetic mutations and amplifications has been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to some classic cytotoxics and targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex machinations and interactions. This knowledge has enabled the evolution of rationally designed drugs targeting elements of this pathway. It is important that the development of suitable biomarkers continues in parallel to optimize use of these agents. A new generation of PI3K inhibitors is now entering early clinical trials, with much anticipation that they will add to the growing armamentarium of targeted cancer therapeutics.