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https://www.readbyqxmd.com/read/28486103/tackling-resistance-to-pi3k-inhibition-by-targeting-the-epigenome
#1
Shany Koren, Mohamed Bentires-Alj
Phosphoinositide-3-kinase (PI3K) pathway inhibitors have emerged as promising therapeutic agents for estrogen receptor (ERα)-positive breast cancers. However, incipient resistance limits the clinical benefit. Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERα activity in BYL719-treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28440469/clinical-significance-of-akt2-in-advanced-pancreatic-cancer-treated-with-erlotinib
#2
Eri Banno, Yosuke Togashi, Marco A de Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio
Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0...
April 18, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28390196/pi3k-isoform-inhibition-associated-with-anti-bcr-abl-drugs-shows-in-vitro-increased-anti-leukemic-activity-in-philadelphia-chromosome-positive-b-acute-lymphoblastic-leukemia-cell-lines
#3
Simona Ultimo, Carolina Simioni, Alberto M Martelli, Giorgio Zauli, Camilla Evangelisti, Claudio Celeghini, James A McCubrey, Giorgia Marisi, Paola Ulivi, Silvano Capitani, Luca M Neri
B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28382169/integration-of-receptor-tyrosine-kinases-determines-sensitivity-to-pi3k%C3%AE-selective-inhibitors-in-breast-cancer
#4
Yi-Chao Xu, Xiang Wang, Yi Chen, Si-Meng Chen, Xin-Ying Yang, Yi-Ming Sun, Mei-Yu Geng, Jian Ding, Ling-Hua Meng
PI3Kα-selective inhibitor BYL719 is currently in phase II/III clinical trial for the treatment of breast cancer, but highly variable response has been observed among patients. We sought to discover predictive biomarker for the efficacy of BYL719 by dissecting the proliferative signaling pathway mediated by PI3K in breast cancer. BYL719 concurrently inhibited the phosphorylation of AKT and ERK in PIK3CA-mutated human breast cancer cells. PI3K-regulated ERK phosphorylation was independent of canonical PDK1/AKT/mTOR pathway, while it was associated with RAF/MEK...
2017: Theranostics
https://www.readbyqxmd.com/read/28351565/new-drug-development-in-head-and-neck-squamous-cell-carcinoma-the-pi3-k-inhibitors
#5
REVIEW
Francesca De Felice, Teresa Guerrero Urbano
Over the last few years a number of new different compounds have been developed. They include phosphatidylinositol 3-kinase (PI3-K) inhibitors. Deregulation within the PI3-K pathway is common in head neck squamous cell carcinoma (HNSCC) and it represents a growing area of research. PI3-K inhibitors, including BKM120, PX-866 and BYL719, are being tested in several phase I and phase II studies in patients with locally advanced, recurrent or metastatic disease. This review provides an update of published clinical trials and highlights the challenges of PI3-K inhibitors in HNSCC...
April 2017: Oral Oncology
https://www.readbyqxmd.com/read/28230287/therapeutic-potential-of-targeting-pi3k-akt-pathway-in-treatment-of-colorectal-cancer-rational-and-progress
#6
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
https://www.readbyqxmd.com/read/28194032/tumour-specific-pi3k-inhibition-via-nanoparticle-targeted-delivery-in-head-and-neck-squamous-cell-carcinoma
#7
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
https://www.readbyqxmd.com/read/28119489/pi3k-inhibitors-synergize-with-fgfr-inhibitors-to-enhance-antitumor-responses-in-fgfr2-mutant-endometrial-cancers
#8
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
https://www.readbyqxmd.com/read/27903677/combined-inhibition-of-both-p110%C3%AE-and-p110%C3%AE-isoforms-of-phosphatidylinositol-3-kinase-is-required-for-sustained-therapeutic-effect-in-pten-deficient-er-breast-cancer
#9
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 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. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27639383/addition-of-the-p110%C3%AE-inhibitor-byl719-overcomes-targeted-therapy-resistance-in-cells-from-her2-positive-pten-loss-breast-cancer
#10
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
https://www.readbyqxmd.com/read/27604488/systematic-functional-characterization-of-resistance-to-pi3k-inhibition-in-breast-cancer
#11
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
https://www.readbyqxmd.com/read/27602501/specific-inhibition-of-p110%C3%AE-subunit-of-pi3k-putative-therapeutic-strategy-for-kras-mutant-colorectal-cancers
#12
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
https://www.readbyqxmd.com/read/27435925/upstream-and-downstream-co-inhibition-of-mitogen-activated-protein-kinase-and-pi3k-akt-mtor-pathways-in-pancreatic-ductal-adenocarcinoma
#13
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
https://www.readbyqxmd.com/read/27259258/multi-kinase-inhibitors-interact-with-sildenafil-and-erbb1-2-4-inhibitors-to-kill-tumor-cells-in-vitro-and-in-vivo
#14
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
https://www.readbyqxmd.com/read/27126994/a-phase-ib-study-of-alpelisib-byl719-a-pi3k%C3%AE-specific-inhibitor-with-letrozole-in-er-her2-metastatic-breast-cancer
#15
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
https://www.readbyqxmd.com/read/27048245/activation-of-igf1r-p110%C3%AE-akt-mtor-confers-resistance-to-%C3%AE-specific-pi3k-inhibition
#16
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
https://www.readbyqxmd.com/read/26864072/integrative-modeling-of-multi-omics-data-to-identify-cancer-drivers-and-infer-patient-specific-gene-activity
#17
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
https://www.readbyqxmd.com/read/26793003/pi3k-inhibitors-as-new-cancer-therapeutics-implications-for-clinical-trial-design
#18
REVIEW
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
https://www.readbyqxmd.com/read/26637981/somatic-activating-pik3ca-mutations-cause-venous-malformation
#19
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
https://www.readbyqxmd.com/read/26490311/analysis-of-mtor-gene-aberrations-in-melanoma-patients-and-evaluation-of-their-sensitivity-to-pi3k-akt-mtor-pathway-inhibitors
#20
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
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