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Afsane Bahrami, Majid Khazaei, Malihe Hasanzadeh, Soodabeh ShahidSales, Mona Joudi Mashhad, Marjaneh Farazestanian, Hamid Reza Sadeghnia, Majid Rezayi, Mina Maftouh, Seyed Mahdi Hassanian, Amir Avan
PI3K/AKT/mTOR signaling pathway is one of the key dysregulated pathways in different tumor types, including colorectal cancer (CRC). Activation of this pathway is shown to be related with cellular transformation, tumor progression, cell survival and drug resistance. There is growing body of data evaluating the value of PI3K/AKT/mTOR inhibitors in CRC (e.g., BEZ235, NVP-BEZ235, OSI-027, everolimus, MK-2206, KRX-0401, BYL719 and BKM120). This report summarizes the current knowledge about PI3K/AKT pathway and its cross talk with ERK/MAPK and mTOR pathways with particular emphasis on the value of targeting this pathway as a potential therapeutic target in treatment of colorectal cancer...
February 23, 2017: Journal of Cellular Biochemistry
Aviram Mizrachi, Yosi Shamay, Janki Shah, Samuel Brook, Joanne Soong, Vinagolu K Rajasekhar, John L Humm, John H Healey, Simon N Powell, José Baselga, Daniel A Heller, Adriana Haimovitz-Friedman, Maurizio Scaltriti
Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu...
February 13, 2017: Nature Communications
Leisl Packer, Xinyan Geng, Vanessa F Bonazzi, Robert Ju, Clare Mahon, Margaret C Cummings, Sally-Anne Stephenson, Pamela M Pollock
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer (EC). ECs display hyper-activation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA and PIK3R1. FGFR2, as well as the PI3K pathway, have emerged as potential therapeutic targets in EC. Activation of the PI3K pathway is seen in >90% of FGFR2mutant ECs. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719...
January 23, 2017: Molecular Cancer Therapeutics
Sarah R Hosford, Lloye M Dillon, Stephanie J Bouley, Rachele Rosati, Wei Yang, Vivian S Chen, Eugene Demidenko, Rocco P Morra, Todd W Miller
PURPOSE: Determine the roles of the phosphatidylinositol 3-kinase (PI3K) isoforms p110α and p110β in PTEN-deficient, estrogen receptor α (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors. EXPERIMENTAL DESIGN: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110α inhibitor BYL719, the p110β inhibitor GSK2636771, or combinations...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chen Zhang, Bingfei Xu, Pian Liu
Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine...
November 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Xiuning Le, Rajee Antony, Pedram Razavi, Daniel J Treacy, Flora Luo, Mahmoud Ghandi, Pau Castel, Maurizio Scaltriti, José Baselga, Levi A Garraway
PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner...
October 2016: Cancer Discovery
Maria Sofia Fernandes, Soraia Melo, Sérgia Velho, Patrícia Carneiro, Fátima Carneiro, Raquel Seruca
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. It is often associated with activating mutations in KRAS leading to deregulation of major signaling pathways as the RAS-RAF-MAPK and PI3K-Akt. However, the therapeutic options for CRC patients harboring somatic KRAS mutations are still very limited. It is therefore urgent to unravel novel therapeutic approaches for those patients. In this study, we have awarded PI3K p110α a key role in CRC cells harboring KRAS/PIK3CA mutations or KRAS mutations alone...
October 18, 2016: Oncotarget
Matthew H Wong, Aiqun Xue, Robert C Baxter, Nick Pavlakis, Ross C Smith
BACKGROUND: Extensive cross talk exists between PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, and both are upregulated in pancreatic ductal adenocarcinoma (PDAC). Our previous study suggested that epidermal growth factor receptor inhibitor erlotinib which acts upstream of these pathways acts synergistically with PI3K inhibitors in PDAC. Horizontal combined blockade upstream and downstream of these two pathways is therefore explored. METHODS: Erlotinib paired with PI3K inhibitor (BYL719) was tested against erlotinib plus dual PI3K/mTOR inhibitor BEZ-235, and MEK inhibitor (PD98059) plus BEZ235, on five primary PDAC cell lines and on two pairs of parent and erlotinib-resistant (ER) cell lines...
July 2016: Neoplasia: An International Journal for Oncology Research
Laurence Booth, Thomas Albers, Jane L Roberts, Mehrad Tavallai, Andrew Poklepovic, Iryna O Lebedyeva, Paul Dent
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization...
June 28, 2016: Oncotarget
Ingrid A Mayer, Vandana G Abramson, Luigi Formisano, Justin M Balko, Mónica V Estrada, Melinda E Sanders, Dejan Juric, David Solit, Michael F Berger, Helen H Won, Yisheng Li, Lewis C Cantley, Eric Winer, Carlos L Arteaga
PURPOSE: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy. EXPERIMENTAL DESIGN: Twenty-six patients received letrozole and alpelisib daily...
January 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Cedric Leroy, Pedro Ramos, Karen Cornille, Debora Bonenfant, Christine Fritsch, Hans Voshol, Mohamed Bentires-Alj
BACKGROUND: The PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected. METHODS: In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors...
April 5, 2016: Breast Cancer Research: BCR
Ana B Pavel, Dmitriy Sonkin, Anupama Reddy
BACKGROUND: High throughput technologies have been used to profile genes in multiple different dimensions, such as genetic variation, copy number, gene and protein expression, epigenetics, metabolomics. Computational analyses often treat these different data types as independent, leading to an explosion in the number of features making studies under-powered and more importantly do not provide a comprehensive view of the gene's state. We sought to infer gene activity by integrating different dimensions using biological knowledge of oncogenes and tumor suppressors...
February 11, 2016: BMC Systems Biology
Cristian Massacesi, Emmanuelle Di Tomaso, Patrick Urban, Caroline Germa, Cornelia Quadt, Lucia Trandafir, Paola Aimone, Nathalie Fretault, Bharani Dharan, Ranjana Tavorath, Samit Hirawat
The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy...
2016: OncoTargets and Therapy
Nisha Limaye, Jaakko Kangas, Antonella Mendola, Catherine Godfraind, Matthieu J Schlögel, Raphael Helaers, Lauri Eklund, Laurence M Boon, Miikka Vikkula
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations...
December 3, 2015: American Journal of Human Genetics
Yan Kong, Lu Si, Yiqian Li, Xiaowen Wu, Xiaowei Xu, Jie Dai, Huan Tang, Meng Ma, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Jun Guo
PURPOSE: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K-AKT-mTOR pathway inhibitors. EXPERIMENTAL DESIGN: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator-like effector nucleases technique...
February 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Alexander James, Lars Blumenstein, Ulrike Glaenzel, Yi Jin, Arnold Demailly, Annamaria Jakab, Regine Hansen, Katharine Hazell, Anuradha Mehta, Lucia Trandafir, Piet Swart
PURPOSE: To determine the pharmacokinetics of the p110α-selective inhibitor alpelisib (BYL719) in humans, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation. METHODS: Four healthy male volunteers received a single oral dose of [(14)C]-labeled alpelisib (400 mg, 2.78 MBq). Blood, urine, and feces samples were collected throughout the study. Total radioactivity was measured by liquid scintillation counting, and metabolites were quantified and identified by radiometry and mass spectrometry...
October 2015: Cancer Chemotherapy and Pharmacology
Chi Hang Wong, Brigette Buig Yue Ma, Hio Teng Cheong, Connie Wun Chun Hui, Edwin Pun Hui, Anthony Tak Cheung Chan
Nasopharyngeal carcinoma (NPC) is endemic to Southeast Asia and over 40% of NPC tissues harbor PIK3CA amplifications. This study aims to study the preclinical activity of a novel PI3K inhibitor, BYL719, in 6 NPC cell lines: C666-1, CNE-2, HK1, HK1-EBV, HONE-1 and HONE-1-LMP1. Over 70% of growth inhibition was attained when NPC cell lines were exposed to increasing concentrations of BYL719, with IC50 values at the low micro-molar range. Two BYL719-sensitive cell lines that harbor PIK3CA mutations, CNE-2 and HONE-1, were selected for further analysis on the effect of BYL719 on cell cycle progression, apoptosis and PI3K signaling...
2015: American Journal of Cancer Research
Mara A Bonelli, Andrea Cavazzoni, Francesca Saccani, Roberta R Alfieri, Federico Quaini, Silvia La Monica, Maricla Galetti, Daniele Cretella, Cristina Caffarra, Denise Madeddu, Caterina Frati, Costanza Annamaria Lagrasta, Angela Falco, Pietro Rossetti, Claudia Fumarola, Marcello Tiseo, Pier Giorgio Petronini, Andrea Ardizzoni
A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110α subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two-dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA-mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model...
August 2015: Molecular Cancer Therapeutics
Ana Bosch, Zhiqiang Li, Anna Bergamaschi, Haley Ellis, Eneda Toska, Aleix Prat, Jessica J Tao, Daniel E Spratt, Nerissa T Viola-Villegas, Pau Castel, Gerard Minuesa, Natasha Morse, Jordi Rodón, Yasir Ibrahim, Javier Cortes, Jose Perez-Garcia, Patricia Galvan, Judit Grueso, Marta Guzman, John A Katzenellenbogen, Michael Kharas, Jason S Lewis, Maura Dickler, Violeta Serra, Neal Rosen, Sarat Chandarlapaty, Maurizio Scaltriti, José Baselga
Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes...
April 15, 2015: Science Translational Medicine
Moshe Elkabets, Evangelos Pazarentzos, Dejan Juric, Qing Sheng, Raphael A Pelossof, Samuel Brook, Ana Oaknin Benzaken, Jordi Rodon, Natasha Morse, Jenny Jiacheng Yan, Manway Liu, Rita Das, Yan Chen, Angela Tam, Huiqin Wang, Jinsheng Liang, Joseph M Gurski, Darcy A Kerr, Rafael Rosell, Cristina Teixidó, Alan Huang, Ronald A Ghossein, Neal Rosen, Trever G Bivona, Maurizio Scaltriti, José Baselga
Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719...
April 13, 2015: Cancer Cell
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