Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.
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PMID:The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments. 3145 Jun 18

Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 antibody drug, is the first-line therapy for human epidermal growth factor receptor 2-positive breast and gastric cancer. For breast cancer, the benefit of continuous treatment with trastuzumab after it becomes refractory to first-line therapy has been demonstrated. However, it is unclear whether trastuzumab can show similar efficacy as a second-line treatment for gastric cancer. Here, we report that trastuzumab in combination with paclitaxel exhibits increased antitumor efficacy even for trastuzumab-resistant xenografted tumors. We derived the trastuzumab-resistant models from previously established human epidermal growth factor receptor 2-positive gastric cancer patient-derived cells. Human epidermal growth factor receptor 2 expression, PIK3CA mutation, and phosphatase and tensin homolog expression in these resistant models was equivalent to those in the trastuzumab-sensitive parental model, whereas cyclin-dependent kinase inhibitors, such as p16, p15, and p21, were downregulated. Trastuzumab in combination with paclitaxel enhanced antitumor activity in both the sensitive and resistant models. In the trastuzumab-sensitive model, the combination of trastuzumab and paclitaxel resulted in suppression of the AKT-p27-retinoblastoma protein pathway and induction of apoptosis. Although this combination did not suppress retinoblastoma protein phosphorylation in the trastuzumab-resistant model, it did markedly decrease epidermal growth factor receptor and human epidermal growth factor receptor 2 phosphorylation and further enhance paclitaxel-mediated apoptosis. These results suggested that trastuzumab in combination with paclitaxel can still exert more potent antitumor efficacy than each agent alone in trastuzumab-resistant models, providing evidence that trastuzumab remains beneficial in the treatment of trastuzumab-resistant tumors.
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PMID:Trastuzumab in combination with paclitaxel enhances antitumor activity by promoting apoptosis in human epidermal growth factor receptor 2-positive trastuzumab-resistant gastric cancer xenograft models. 3163

nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886's tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886's impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886- cells) have activated AKT and altered expression of cell cycle genes. nc886- cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886- cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.
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PMID:A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression. 3222 25


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