Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling

Will, Marie; Qin, Alice Can Ran; Toy, Weiyi; Yao, Zhan; Rodrik-Outmezguine, Vanessa; Schneider, Claudia; Huang, Xiaodong; Monian, Prashant; Jiang, Xuejun; Stanchina, Elisa de; Baselga, José; Liu, Ningshu; Chandarlapaty, Sarat; Rosen, Neal

doi:10.1158/2159-8290.cd-13-0611

Cited by 174 publications

(180 citation statements)

References 32 publications

(45 reference statements)

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“…Cleaved PARP was also observed as a similarly early onset event (Fig. 1E), suggesting that induction of apoptosis contributes to the cell death phenotype, as reported for other PI3K-inhibitors (27). This transient pathway inhibition is consistent with pathway feedback and reactivation (17,18) and was similarly observed in a timecourse study in MCF7 cells (Supplementary Fig.…”

Section: Azd8835 Selectively Inhibits Pi3ka and Pi3kdsupporting

confidence: 83%

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Hudson

Hancox

Trigwell

et al. 2016

Molecular Cancer Therapeutics

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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.

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Section: Azd8835 Selectively Inhibits Pi3ka and Pi3kdsupporting

confidence: 83%

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Hudson

Hancox

Trigwell

et al. 2016

Molecular Cancer Therapeutics

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“…Furthermore, in Rasinduced oncogenic transformation, PTEN apoptotic function is suppressed via the Raf-Mek-Erk pathway (37). Recent publications using human breast cancer cell lines support the notion that PI3K inhibition can involve an ERK-dependent component (38,39). In one study, this effect was apparently mediated by the phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1), which activates Rac1, leading to MAPK pathway activation.…”

Section: Discussionmentioning

confidence: 99%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracyclineregulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

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“…LY3023414 shows dose-dependent inhibition of phosphorylation of PI3K/Akt/mTOR pathway downstream substrates for 4 to 6 hours in vivo, reflecting the drug's half-life of 2 hours, and leads to potent antitumor activity in tumor xenograft models (7). An intermittent, "quick-on/quickoff" target engagement mechanism has been suggested to enhance clinical tolerability of PI3K/mTOR inhibitors as well as potentially reduce the emergence of compensatory resistance mechanisms (7,8). The pharmacokinetic parameters of LY3023414 in rats and dogs suggest that the drug is extensively absorbed at relevant doses and subsequently cleared in part via oxidative metabolism by CYP enzymes (7).…”

Section: Introductionmentioning

confidence: 99%

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Bendell

Varghese

Hyman

et al. 2018

Clinical Cancer Research

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Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414.Experimental Design: A 3þ3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity.Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ! 90% target inhibition at doses !150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%.Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. Clin Cancer Res; 1-10. Ó2018 AACR.

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Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling

Cited by 174 publications

References 32 publications

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

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