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Inhibition of the -Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.
Yang T, Meoli DF, Moslehi J, Roden DM
(2018) J Pharmacol Exp Ther 365: 460-466
MeSH Terms: Action Potentials, Animals, Arrhythmias, Cardiac, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Electrophysiological Phenomena, Enzyme Inhibitors, Female, Heart, Mice, Mice, Inbred C57BL, Myocytes, Cardiac, Phosphoinositide-3 Kinase Inhibitors, Sodium
Show Abstract · Added April 22, 2018
Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac late sodium current (I). Previous studies in mice implicate the PI3K- isoform in arrhythmia susceptibility. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on I and action potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO). Chronic exposure (10-100 nM; 5-48 hours) to PI3K--specific subunit inhibitors BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased I in -transfected CHO cells and mouse cardiomyocytes. The specific inhibitors (10-100 nM for 5 hours) markedly prolonged APs and generated triggered activity in mouse cardiomyocytes (9/12) but not in controls (0/6), and BKM120 caused similar effects (3/6). The inclusion of water-soluble PIP3, a downstream effector of the PI3K signaling pathway, in the pipette solution reversed these arrhythmogenic effects. By contrast, inhibition of PI3K-, -, and - isoforms did not alter I or APs. We conclude that inhibition of cardiac PI3K- is arrhythmogenic by increasing I and this effect is not seen with inhibition of other PI3K isoforms. These results highlight a mechanism underlying potential cardiotoxicity of PI3K- inhibitors.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
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15 MeSH Terms
PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses.
Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A
(2017) Clin Cancer Res 23: 3371-3384
MeSH Terms: Aminopyridines, Animals, Cell Line, Tumor, Cell Proliferation, Class Ib Phosphatidylinositol 3-Kinase, Female, Humans, Immunity, Cellular, Mammary Neoplasms, Animal, Mice, Morpholines, Neoplasm Metastasis, Phosphoinositide-3 Kinase Inhibitors, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added January 4, 2017
Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity. The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or -null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and versus mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice. Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of in the host. The antitumor effect of loss in host, but not tumor, was partially reversed by CD8 T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone. PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. .
©2016 American Association for Cancer Research.
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18 MeSH Terms
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L
(2016) Nat Rev Clin Oncol 13: 674-690
MeSH Terms: Androgen Antagonists, BRCA2 Protein, Biomarkers, Tumor, Clinical Trials as Topic, Female, Humans, Immune System, Immunotherapy, Mitogen-Activated Protein Kinases, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells, Phosphoinositide-3 Kinase Inhibitors, Poly(ADP-ribose) Polymerase Inhibitors, Prognosis, Triple Negative Breast Neoplasms, Ubiquitin-Protein Ligases
Show Abstract · Added April 6, 2017
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.
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A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL
(2017) Clin Cancer Res 23: 26-34
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Aromatase Inhibitors, Biomarkers, Tumor, Breast Neoplasms, Cell Line, Tumor, DNA Mutational Analysis, Female, Humans, In Situ Hybridization, Fluorescence, Letrozole, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Staging, Nitriles, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Receptor, ErbB-2, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Estrogen, Thiazoles, Treatment Outcome, Triazoles
Show Abstract · Added April 6, 2017
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. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.
RESULTS - Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.
©2016 American Association for Cancer Research.
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Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers.
Young CD, Arteaga CL, Cook RS
(2015) Breast Cancer Res 17: 148
MeSH Terms: Apoptosis, Autophagy, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Humans, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Signal Transduction
Show Abstract · Added April 15, 2019
INTRODUCTION - Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25% of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear.
METHODS - We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers.
RESULTS - Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing.
CONCLUSIONS - These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.
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Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
Cohen MR, Johnson WM, Pilat JM, Kiselar J, DeFrancesco-Lisowitz A, Zigmond RE, Moiseenkova-Bell VY
(2015) Mol Cell Biol 35: 4238-52
MeSH Terms: Animals, Calcium, Calcium Channels, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, HEK293 Cells, Humans, MAP Kinase Signaling System, Nerve Growth Factor, Neurites, Neurogenesis, Neurons, PC12 Cells, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, RNA Interference, RNA, Small Interfering, Rats, Receptor, trkA, TRPV Cation Channels, rab GTP-Binding Proteins
Show Abstract · Added April 24, 2017
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.
Dong J, Dong J, Lin J, Wang B, He S, Wu C, Kushwaha KK, Mohabeer N, Su Y, Fang H, Huang K, Li D
(2015) Cell Physiol Biochem 35: 160-74
MeSH Terms: Androstadienes, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Chromones, Cytokines, Disease Models, Animal, Ferric Compounds, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, P-Selectin, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, Signal Transduction, Wortmannin
Show Abstract · Added January 20, 2015
AIMS - Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway.
METHODS AND RESULTS - Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor.
CONCLUSION - This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.
© 2015 S. Karger AG, Basel.
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26 MeSH Terms
LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.
Schwarz LJ, Fox EM, Balko JM, Garrett JT, Kuba MG, Estrada MV, González-Angulo AM, Mills GB, Red-Brewer M, Mayer IA, Abramson V, Rizzo M, Kelley MC, Meszoely IM, Arteaga CL
(2014) J Clin Invest 124: 5490-502
MeSH Terms: Amino Acid Substitution, Aminopyridines, Animals, Breast Neoplasms, Dasatinib, Drug Resistance, Neoplasm, Drug Synergism, Estrogen Receptor Modulators, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Morpholines, Mutation, Missense, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, Receptors, Estrogen, Thiazoles, Xenograft Model Antitumor Assays, src Homology Domains, src-Family Kinases
Show Abstract · Added February 16, 2016
Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.
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26 MeSH Terms
PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors.
Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gómez H, Arteaga CL, Mills GB, Sanders ME, Pietenpol JA
(2014) Breast Cancer Res 16: 406
MeSH Terms: Androgen Receptor Antagonists, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Class I Phosphatidylinositol 3-Kinases, Cluster Analysis, Dihydrotestosterone, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Mutation, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors, Receptors, Androgen, Signal Transduction, TOR Serine-Threonine Kinases, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added January 20, 2015
INTRODUCTION - Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC.
METHODS - We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability.
RESULTS - PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects.
CONCLUSIONS - While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.
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23 MeSH Terms
Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y, Cantley LC, Winer E, Arteaga CL
(2014) J Clin Oncol 32: 1202-9
MeSH Terms: Adult, Aged, Aminopyridines, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Fluorodeoxyglucose F18, Humans, Letrozole, Middle Aged, Morpholines, Multimodal Imaging, Nitriles, Phosphoinositide-3 Kinase Inhibitors, Positron-Emission Tomography, Protein Kinase Inhibitors, Radiopharmaceuticals, Receptor, ErbB-2, Receptors, Estrogen, Tomography, X-Ray Computed, Triazoles
Show Abstract · Added March 27, 2014
PURPOSE - Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.
PATIENTS AND METHODS - Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.
RESULTS - Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.
CONCLUSION - The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.
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26 MeSH Terms