SUMMARY In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.
Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC 50 , 4 nmol/L), erbB2 (IC 50 , 3 nmol/L), and erbB3 (IC 50 , 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159-69. ©2010 AACR.The erbB receptor family is composed of four related receptor tyrosine kinases [epidermal growth factor receptor (EGFR, erbB1), erbB2 (human epidermal growth factor receptor 2, HER2), erbB3 (HER3), and erbB4 (HER4)]. ErbB2 lacks ligand-binding capacity and erbB3 is intrinsically inactive as a kinase. There are two main ligand classes: the first bind specifically to EGFR whereas the second includes the neu differentiation factors, or heregulins, which bind erbB3 and erbB4 (1). In cancer, activation of erbB2 may arise by (a) receptor overexpression inducing homodimerization and (b) receptor heterodimerization with another family member, of which erbB3 is considered to be the preferred and most oncogenic partner (2).Homodimerization and/or heterodimerization of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival (3, 4). The deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, in...
Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.
The PIK3CA gene, encoding the p110a catalytic unit of PI3Ka, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Ka is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Ka and PI3Kd with selectivity versus PI3Kb, PI3Kg, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER þ ) breast cancer cell lines BT474, MCF7, and T47D (submmol/L GI 50 s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER þ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877-89. Ó2016 AACR.
Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure− activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer. KEYWORDS: AZD8931, HER receptor family, kinase inhibitor T he HER receptor family comprises four related receptor tyrosine kinases (EGFR, HER2, HER3, and HER4) and is associated with two main ligand classes:1 the first class binds to EGFR, and the second class, which includes heregulins, binds to HER3 and HER4. HER2 lacks ligand-binding capacity. Homo-and/or heterodimerization of HER receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival.2,3 Deregulation of HER family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, including those of the lung, head and neck, and breast. 4,5 Therefore, the HER receptor family represents a class of rational targets for anticancer drug development, and a number of small molecules targeting EGFR and HER2 are now clinically available, including gefitinib, erlotinib, and lapatinib (Figure 1). More recently, the importance of the composition of functional HER dimeric units in tumor cell signaling has become apparent in diverse systems, modeling both liganddependent and independent drives. Careful profiling of all four HER receptors has differentiated their molecular function, 6 and HER3 has been found to have a central role in the transduction of signals to the phosphatidylinositol 3-kinase (PI3K) pathway, thus mediating cell survival signals for EGFR, HER2, and potentially HER4. 7 We hypothesized that simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the current HER therapeutic agents are ineffective or only modestly active.Previous projects at AstraZeneca looking for selective EGFR 8−11 or HER2 12−15 inhibitors led to several preclinical and/or clinical candidates, including gefitinib, 8 a selective EGFR kinase inhibitor. Screening our collection of EGFR kinase inhibitors for HER2 activity identified a...
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
AZD8186 inhibits Pi3K isoforms Pi3Kβ and δ, with selectivity over Pi3Kα and γ. In solid tumours Pi3Kβ drives tumour growth when the tumour suppressor PTEN is deleted, mutated or downregulated. It also mediates signals from specific GPCR receptors. Pi3Kδ signals downstream of the B-cell receptor, creating potential for targeted treatment of haematological malignancies such as CLL, MCL & indolent NHL and possibly DLBCL. AZD8186 is differentiated from many other agents that target Pi3K family members as it isn't likely to impact glucose control. AZD8186 has single agent activity in a range of models, although maximal benefit is anticipated when used in combination. Loss of PTEN mediated control, and hence dependency on PI3Kβ occurs in many solid tumour types, and is altered in up to 40-50% of tumours in some individual disease states. Commonly PTEN dysregulation is associated with other activation of other signaling pathways. To explore this we have combined AZD8186 with a number of different agents. In HCC70 (triple negative breast cancer) and PC3 (prostate cancer) xenografts combination of AZD8186 (25mg/kg bid) with single dose docetaxel (15mg/kg) gives >90% tumour growth inhibition (TGI), compared to 40-50% with docetaxel alone. AZD8186 also combines with other targeted agents. In HCC70, AZD8186 (25mg/kg bid) combined with selumetinib (10mg/kg) gave 94% TGI compared to 66%, and 47% with each single agent. In combination with AZD2014 (mTORC1/2 inhibitor) (15mg/kg qd) in HCC70 xenografts AZD8186 (25mg/kg bid) gave regressions (-23%) compared to TGI of 87% and 77% for each agent alone. In 786-0 (renal cancer) xenografts AZD8186 (12.5mg/kg bid) and AZD2014 (15mg/kg qd) gave regression of -82% compared to TGI of 33% and regression of -39% with each agent alone. This data establishes the potential for AZD8186 to be used in combination with a number of different agents including the ability to customise dose and schedule to optimise both tolerability as well as anti-tumour effects. Further exploration of the combination opportunities for AZD8186 with other molecular targeted agents would inform on the potential for inhibitors of Pi3Kβ and δ to give benefit in different tumour types. Citation Format: Simon T. Barry, Kathryn Cronin, Marie Cumberbatch, Rebecca Ellston, Emily Foster, Urs Hancox, Lyndsey Hanson, Liz Harrington, Carol Lenaghan, Stefan Symeonides, Cath Trigwell, Lara Ward. The Pi3Kβ/δ inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2014-4249
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