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AKT/mTOR/HER/PI3K family genes and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150576 | GEO | 2020/09/20

REPOSITORIES: GEO

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AKT/mTOR/HER/PI3K family proteins and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of phosphorylation of AKT kinase substrates, in pre-defined analyses we assessed 26 well known proteins/phospho-proteins in the HER-AKT-mTOR pathway to test their association with pCR in the MK2206 arm, in both HER2+ and HER2- subsets. We specifically used laser capture microdissection (LCM)- enriched tumor epithelium cell isolates from the clinical biopsy specimens as the sample input for all protein pathway activation analysis, which has been shown to be critical in accurate measurement of ubiquitously expressed and activated signaling proteins. To the best of our knowledge, this work represents the first rigorous study of association between direct measurement of AKT pathway activation using phospho-protein activation levels and response to MK2206 performed in early stage breast cancer patients.

2020-09-20 | GSE150575 | GEO

AKT/mTOR/HER/PI3K family genes as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of AKT kinase substrates, in pre-defined analyses we assessed 10 genes in the HER-AKT-mTOR pathway to test their association with pCR (complete pathologic response) in the MK2206 arm, in both HER2+ and HER2- subsets. We also tested 9 genes genes previously associated with response to MK2206 in vitro and in the HER2+ metastatic setting, and performed exploratory association analyses using whole-transcriptome data to identify additional predictive signals outside the HER-AKT-mTOR pathway.

2020-09-20 | GSE149322 | GEO

AKT/mTOR/HER/PI3K family genes and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL

Project description:AKT/mTOR/HER/PI3K family genes and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL

| PRJNA632842 | ENA

AKT/mTOR/HER/PI3K family proteins and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:AKT/mTOR/HER/PI3K family proteins and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

| PRJNA632851 | ENA

AKT/mTOR/HER/PI3K family genes as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:AKT/mTOR/HER/PI3K family genes as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

| PRJNA629770 | ENA

PI3K/AKT/mTOR pathway in pulmonary carcinoid tumours.

Project description:The present study examined the expression of mammalian target of rapamycin (mTOR) and mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway in 54 patients with typical carcinoid tumours (TC) or atypical carcinoid tumours (AC). In total, 54 bronchopulmonary neuroendocrine tumour (NET) surgical specimens, consisting of 17 TC, 8 AC, 17 large-cell neuroendocrine carcinoma (LCNEC), and 12 small-cell lung carcinoma (SCLC) samples, were tested for mTOR by immunohistochemistry, and 104 exon sites were tested in the PI3K/AKT/mTOR pathway by nested polymerase chain reaction. It was found that the positive rates for mTOR expression in TC/AC and LCNEC/SCLC were 60 (15/25) and 55.2% (16/29), respectively. In total, 4 missense mutations were found in 3 patients with TC/AC, including mutations in exon 48 of mTOR (c.6667C>T), exon 21 of tuberous sclerosis complex (TSC) 1 (c.2765G>A), and exons 12 (c.1265C>T) and 19 (c.2148C>T) of TSC2. To the best of our knowledge, mutations in exon 48 of mTOR and exon 21 of TSC1 have not been previously reported. Tissues from patients with single mutations exhibited strong positive mTOR immunohistochemical staining, and tissues from patients with double mutations were weakly positive. The same mutations were not observed in SCLC or LCNEC. In conclusion, gene mutations were observed and an association between the gene mutations and mTOR expression were indicated in the PI3K/AKT/mTOR pathway in TC/AC tumours. Those mutations may be driver genes and treatment targets.

| S-EPMC5529984 | biostudies-other

MK2206 enhances the cytocidal effects of bufalin in multiple myeloma by inhibiting the AKT/mTOR pathway.

Project description:Despite the development of promising cancer therapeutic drugs, multiple myeloma (MM) remains an incurable disease. Bufalin is a bufanolide steroid compound of the traditional Chinese medicine Chan Su that was previously shown to exert growth suppression effects on myeloma cell lines. Previous studies conducted by our group demonstrated that bufalin activated the AKT/mTOR pathway in myeloma cells, which is considered an essential pathway to disease progression and is related to drug resistance in MM. In view of the significant role of AKT in MM, the allosteric AKT inhibitor MK2206 was selected in order to enhance the antitumor effects of bufalin in different MM cell lines (NCI-H929, U266, LP-1 and RPMI8226). The data indicated that MK2206 enhanced the cytotoxicity of bufalin in MM cells, via the suppression of cellular proliferation and the induction of apoptosis, as demonstrated by cleavage of apoptosis-related proteins. This effect was further noted in the presence of exogenous interleukin-6 and/or following the co-culture of MM cells with bone marrow stromal cells (BMSC). This process was associated with the inhibition of the AKT/mTOR pathway. The combination of bufalin with MK2206 reduced the secretion of IL-6 in U266 cells. The combined treatment exhibited similar anti-MM effects in bortezomib-resistant cell lines (NCI-H929R, U266R). In addition to the in vitro cell line models, the synergistic effect was noted in primary MM cells and in MM xenografts of BALB-c and NOD-SCID mice. In conclusion, the data suggested that MK2206 significantly enhanced the cytocidal effects of bufalin in MM cells, regardless of the sensitivity to bortezomib, via the inhibition of the AKT/mTOR pathway. The study provided the basis of a promising treatment approach for MM.

| S-EPMC5520709 | biostudies-literature

PI3K/Akt/mTOR inhibitors in breast cancer.

Project description:Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase I to III trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR (PAM) pathway.

| S-EPMC4706528 | biostudies-literature

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer.

Project description:Phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) (PAM) pathways play important roles in breast tumorigenesis and confer worse prognosis in breast cancer patients. The inhibitors targeting three key nodes of these pathways, PI3K, AKT and mTOR, are continuously developed. For breast cancer patients to truly benefit from PAM pathway inhibitors, it is necessary to clarify the frequency and mechanism of abnormal alterations in the PAM pathway in different breast cancer subtypes, and further explore reliable biomarkers to identify the appropriate population for precision therapy. Some PI3K and mTOR inhibitors have been approved by regulatory authorities for the treatment of specific breast cancer patient populations, and many new-generation PI3K/mTOR inhibitors and AKT isoform inhibitors have also been shown to have good prospects for cancer therapy. This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.

| S-EPMC9406657 | biostudies-literature

Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs.

Project description:It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.

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