Supplementary Figure S2 from Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for <i>PIK3CA</i>-Dependent Breast Cancers
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posted on 2023-04-03, 15:42 authored by Kevin Hudson, Urs J. Hancox, Cath Trigwell, Robert McEwen, Urszula M. Polanska, Myria Nikolaou, Pablo Morentin Gutierrez, Alvaro Avivar-Valderas, Oona Delpuech, Phillippa Dudley, Lyndsey Hanson, Rebecca Ellston, Alys Jones, Marie Cumberbatch, Sabina C. Cosulich, Lara Ward, Francisco Cruzalegui, Stephen Green<p>Timecourses showing transient glucose / insulin elevations in mice following AZD8835 dosing.</p>
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ARTICLE ABSTRACT
The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα 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 PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor–positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). 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+ 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. ©2016 AACR.Usage metrics
Keywords
Breast CancerCell CycleSignal transduction pathwaysChemotherapyCombination chemotherapyDrug MechanismsCell cycle mechanisms of anticancer drug actionCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysPharmacologyCellular pharmacologyMolecular pharmacologyPharmacokinetics and pharmacodynamicsSmall Molecule Agents
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