Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer

Elmenier, Fatma M.; Lasheen, Deena S.; Abouzid, Khaled A. M.

doi:10.1016/j.ejmech.2019.111718

Cited by 103 publications

(70 citation statements)

References 101 publications

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“…AKT plays significant roles in cell growth and apoptosis and works as a vital mediator in the ErbB-related pathway. [55][56][57] In addition, the ErbB2-3 heterodimer is the strongest activator of the PI3K/AKT pathway among all the ErbBdimer family members. Cancer and diabetes are closely related to poorly regulated AKT activity.…”

Section: The Egfr-related Pathwaymentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

1,126

821

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Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.

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Section: The Egfr-related Pathwaymentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

1,126

821

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“…40 Accordingly, two rapamycin derivatives (everolimus and temsirolimus) are FDA-approved therapies for cancer, and several second-generation ATP-competitive mTOR inhibitors and a number of dual PI3K/mTOR inhibitors are in development. 41 Interestingly, the mammalian retina shares a special metabolic phenomenon of aerobic glycolysis with neoplastic cells. This is known as the Warburg effect, and is partially mediated by HIF-1α, which is itself regulated by mTORC1.…”

Section: Mtor and Cancermentioning

confidence: 99%

“…61 Omipalisib, a dual PI3K/mTOR inhibitor currently undergoing trials for the systemic treatment of cancer and idiopathic pulmonary fibrosis, has also been evaluated for CNV. 41 In laser-induced CNV mouse models, intravitreal omipalisib (GSK2126458) has been demonstrated to outperform the VEGF inhibitor aflibercept. Oral omipalisib has also been shown to inhibit CNV in the same model but is associated with a systemic diabetogenic effect, probably through blockade of insulin signalling.…”

Section: Exudative Amd and Mtormentioning

confidence: 99%

“…Indeed the PI3K/AKT/mTOR pathway is one of the most frequently activated pathways in cancer and is considered to play a central role in some 30% to 50% of tumours 40 . Accordingly, two rapamycin derivatives (everolimus and temsirolimus) are FDA‐approved therapies for cancer, and several second‐generation ATP‐competitive mTOR inhibitors and a number of dual PI3K/mTOR inhibitors are in development 41 …”

Section: Introductionmentioning

confidence: 99%

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Metabolic pathways in context: mTOR signalling in the retina and optic nerve ‐ A review

Yao

Wijngaarden

2020

Clinical Exper Ophthalmology

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The mechanistic target of rapamycin (mTOR) signalling network plays a key role in growth and development, autophagy, metabolism, inflammation as well as ageing, and it is therefore important in ocular health and disease. mTOR dysregulation has been identified in a range of conditions, including age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, traumatic optic neuropathy and glaucoma. Experimental modulation of the pathway has contributed to the understanding of these diseases and offers the potential for new avenues of therapy. This review discusses the mTOR pathway and its role in health and in diseases of the retina and optic nerve.

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“…PIK3CA involves two main “hotspots” for activating mutations: E545K of the helical domain on exon 9, and H1047R of the kinase domain on exon 20 ( 1 – 9 ). Mutations in AKT1 , and loss-of-function mutations and alterations in PTEN also affect the PI3K pathway, thus promoting cell survival and resistance ( 8 , 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer

et al. 2020

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Background: PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes. Methods: Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the PIK3CA-AKT1-PTEN pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents. Results: Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1,472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2,682 (54.8%) had PTEN alterations ( PTEN mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a PIK3R1 mutation, and 4 (0.08%) a PIK3R2 mutation. Most of the cohort consisted of metastatic sites ( n = 2974, 60.8%), with PIK3CA mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), p < 0.001. Other PIK3CA mutations were identified in 388 (7.9%) specimens, classified as “off-label,” as they were not included in the FDA-approved companion test for PIK3CA mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in PIK3CA-AKT1-PTEN mutated cohorts. Novel concurrent mutations were identified including CDH1 mutations. Conclusions: Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for “off-label” PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.

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Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer

Cited by 103 publications

References 101 publications

Comprehensive review of targeted therapy for colorectal cancer

Comprehensive review of targeted therapy for colorectal cancer

Metabolic pathways in context: mTOR signalling in the retina and optic nerve ‐ A review

Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer

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