Maximising the potential of AKT inhibitors as anti-cancer treatments

Brown, Jessica; Banerji, Udai

doi:10.1016/j.pharmthera.2016.12.001

Cited by 197 publications

(205 citation statements)

References 163 publications

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“…The cases of skin rash and diarrhea were self-limiting and recovered once treatment stopped. These AEs have been noted in Phase 1 studies of other AKT inhibitors, such as the allosteric inhibitor MK2206 or kinase inhibitors such as GSK2141795 and ipatasertib (GDC-0068) (1,(12)(13)(14)(15)(16)(17). Hyperglycemia development was acute and indicative of the inhibitory effect of AZD5363 on AKT, a key regulator of glucose transport and metabolism in peripheral tissues and the liver (17).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinically, sensitivity to AZD5363 has been strongly related to the presence of PIK3CA mutations (4,5), a trend that has also been observed with other inhibitors of the PI3K/AKT/mTOR pathway (6). PIK3CA mutations are found in breast and gynecologic cancers, and evaluation of AZD5363 in these settings is warranted (1).…”

Section: Introductionmentioning

confidence: 94%

“…AKT is a serine/threonine protein kinase that functions as a key node in the phosphatidylinositol-3-kinase (PI3K)/AKT network (also known as the PI3K/AKT/mTOR pathway), with a fundamental role in cell survival and proliferation (1). AKT is overexpressed or activated in a wide range of solid and hematologic malignancies, and aberrant AKT signaling is also associated with resistance to established cancer therapies, as well as advanced disease and/or poor prognosis (2).…”

Section: Introductionmentioning

confidence: 99%

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A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers

Banerji

Dean

Perez-Fidalgo

et al. 2018

Clinical Cancer Research

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111

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Results: Maximum tolerated doses were 320 mg, 480 mg and 640 mg for continuous (n=47), 4/7 (n=21) and 2/7 (n=22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for CTCAE grade ≥3 events, hyperglycemia (20%). The recommended Phase 2 dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the pre-specified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA cohort were met. Author Manuscript Published OnlineFirst on October 24, 2017; DOI: 10.1158/1078-0432.CCR-17-2260 6 Conclusions Statement of translational relevance (144/150 max)AZD5363 is a potent, selective inhibitor of AKT, a key node in the PI3K/AKT/mTOR pathway that is activated in a wide range of malignancies. In vivo, AZD5363 inhibited tumor growth in xenograft models. Preclinically, sensitivity to AZD5363 has been strongly related to the presence of PIK3CA mutations, which are relatively common in breast and gynecologic cancers. Our study, the first-in-human study of AZD5363, showed that at an identified recommended Phase 2 dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. The study is also the first report of a biomarker-stratified cohort (PIK3CA mutations in breast and gynecologic cancers) of patients treated with an AKT inhibitor. Results suggest that future efforts in developing this class of drugs for the treatment of solid tumors, including PIK3CA-mutated breast and gynecologic cancers, will need to be in combination with other anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers

Banerji

Dean

Perez-Fidalgo

et al. 2018

Clinical Cancer Research

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111

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“…A diversity of roles for AKT isoforms is emerging in different cancer types, and understanding these isoform-specific roles will be essential for optimal utilization of the AKT inhibitors already in clinical trials. 40 …”

Section: Discussionmentioning

confidence: 99%

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

Jin

Xie

Ostriker

et al. 2017

ATVB

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Objective Drug-eluting stent delivery of mTORC1 inhibitors is highly effective in preventing intimal hyperplasia following coronary revascularization, but adverse effects limit utility for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell (SMC) differentiation in an AKT2-dependent manner in vitro. Here we investigate the roles of AKT isoforms in intimal hyperplasia. Approach and Results We found that germline or smooth muscle-specific deletion of Akt2 resulted in more severe intimal hyperplasia compared to control mice after arterial denudation injury. Conversely, smooth muscle-specific Akt1 knockout prevented intimal hyperplasia, while germline Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in SMC proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4, inhibiting its binding to the MYOCD promoter. Conclusions Our data reveal opposing roles for AKT isoforms in SMC remodeling. AKT2 is required for rapamycin’s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of myocardin (MYOCD) via FOXO4. Because AKT2 signaling is impaired in diabetes, this work has important implications for rapamycin therapy, particularly in diabetic patients.

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“…Numerous studies have clearly demonstrated that activation of the PI3K/AKT signaling pathway could regulate BIM expression (44,47). The PI3K/AKT signaling pathway triggers a cascade of cell responses, including cell cycle progression, programmed cell death and DNA damage repair in cancer (48). Furthermore, the PI3K/AKT signaling pathway is closely associated with the development and recurrence of cancer (49).…”

Section: Discussionmentioning

confidence: 99%

High BIM mRNA levels are associated with longer survival in advanced gastric cancer

Huang

Zou

et al. 2017

Oncology Letters

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Abstract. Chemotherapy drugs, including 5-fluorouracil (5-FU), oxaliplatin and docetaxel, are commonly used in the treatment of gastric cancer (GC). Apoptosis-relevant genes may be associated with drug resistance. In the present study, the messenger RNA (mRNA) expression levels of B-cell lymphoma 2 interacting mediator of cell death (BIM), astrocyte elevated gene-1 (AEG-1) and AXL receptor tyrosine kinase (AXL) were investigated in 131 advanced GC samples, and the expression levels of these genes were correlated with patients' overall survival (OS). All 131 patients received first-line FOLFOX combination chemotherapy with folinic acid and 5-FU, in which 56 patients were further treated with second-line docetaxel-based chemotherapy. A correlation between the mRNA expression levels of BIM and AEG-1 was observed (r s =0.30; P=0.002). There was no association between the mRNA expression levels of any of the individual genes analyzed and OS in patients only receiving first-line FOLFOX chemotherapy. In a subgroup of patients receiving docetaxel-based second-line chemotherapy, those with high or intermediate levels of BIM exhibited a median OS of 18.2 months [95% confidence interval (CI), 12.8-23.6], compared with 9.6 months (95% CI, 8.9-10.3) in patients with low BIM levels (P=0.008). However, there was no correlation between the mRNA expression levels of AEG-1 or AXL and OS. The risk of mortality was higher in patients with low BIM mRNA levels than in those with high or intermediate BIM mRNA levels (hazard ratio, 2.61; 95% CI, 1.21-5.62; P=0.010). Therefore, BIM may be considered as a biomarker to identify whether patients could benefit from docetaxel-based second-line chemotherapy in GC.

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Maximising the potential of AKT inhibitors as anti-cancer treatments

Cited by 197 publications

References 163 publications

A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers

A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers

Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response

High BIM mRNA levels are associated with longer survival in advanced gastric cancer

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