Abstract:
UNLABELLED:Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE:This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Tanaka K,Babic I,Nathanson D,Akhavan D,Guo D,Gini B,Dang J,Zhu S,Yang H,De Jesus J,Amzajerdi AN,Zhang Y,Dibble CC,Dan H,Rinkenbaugh A,Yong WH,Vinters HV,Gera JF,Cavenee WK,Cloughesy TF,Manning BD,Baldwin AS,Midoi
10.1158/2159-8290.CD-11-0124subject
Has Abstractpub_date
2011-11-01 00:00:00pages
524-38issue
6eissn
2159-8274issn
2159-8290pii
2159-8290.CD-11-0124journal_volume
1pub_type
杂志文章相关文献
Cancer Discovery文献大全abstract::Recent results suggest that tucatinib, when combined with trastuzumab and capecitabine, is effective in patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies: In a phase II trial, the drug extended overall survival and progression-free survival compared w...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2019-135
更新日期:2020-01-01 00:00:00
abstract::A recent study investigated the mechanisms underlying the interaction between olaparib and cediranib in non-BRCA-mutant ovarian cancer. Cediranib may confer sensitivity to olaparib by increasing tumor hypoxia and inhibiting platelet-derived growth factor receptor, which reduces BRCA1/2 and RAD51 expression, thus decre...
journal_title:Cancer discovery
pub_type: 评论,新闻
doi:10.1158/2159-8290.CD-NB2019-064
更新日期:2019-08-01 00:00:00
abstract::In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart di...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-19-0406
更新日期:2019-06-01 00:00:00
abstract::A recent study suggests that natural killer (NK) cells may play an important role in antitumor response to immune checkpoint inhibitors. Researchers used mouse models to show that NK cells respond to PD-1 and PD-L1 inhibitors, information that could be used to develop immunotherapies that tap NK cells to combat cancer...
journal_title:Cancer discovery
pub_type: 评论,新闻
doi:10.1158/2159-8290.CD-NB2018-131
更新日期:2018-12-01 00:00:00
abstract::Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0597
更新日期:2020-07-01 00:00:00
abstract::A new nanoparticle design may make cancer detection possible without the use of molecular markers of tumor cells. The star-shaped probe detected five different cancers in mouse models, according to a new study. By using nanostars to boost surface-enhanced resonance Raman scattering signals, the technique highlighted t...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-022
更新日期:2015-04-01 00:00:00
abstract::Gilead Sciences will buy Kite Pharma-and its autologous CAR T-cell technology-for $11.9 billion. The acquisition will help Gilead build its oncology portfolio and boost its revenues. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-123
更新日期:2017-10-01 00:00:00
abstract::Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-16-1000
更新日期:2017-03-01 00:00:00
abstract::Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent an...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0367
更新日期:2019-12-01 00:00:00
abstract::In a phase Ib trial, a combination of the experimental immunotherapy AM0010, a PEGylated form of the recombinant human cytokine IL10, and the anti-PD-1 checkpoint inhibitor pembrolizumab was well tolerated and effective at controlling tumors in some patients with advanced renal cell carcinoma, non-small cell lung canc...
journal_title:Cancer discovery
pub_type:
doi:10.1158/2159-8290.CD-NB2016-125
更新日期:2016-12-01 00:00:00
abstract::Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and human...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0161
更新日期:2019-09-01 00:00:00
abstract::DNA repair deficiencies are common among cancer cells and represent a potential vulnerability that might be exploited by targeting compensatory repair pathways. However, the identification of synthetically lethal combinations of DNA repair defects, although of significant clinical relevance, has been somewhat anecdota...
journal_title:Cancer discovery
pub_type:
doi:10.1158/2159-8290.CD-14-0316
更新日期:2014-05-01 00:00:00
abstract::Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-20-0328
更新日期:2020-08-25 00:00:00
abstract:UNLABELLED:Knowledge of "actionable" somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy-number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0184
更新日期:2012-01-01 00:00:00
abstract::Data from the KEYNOTE-001 trial show that pembrolizumab improves clinical outcomes for patients with advanced non-small cell lung cancer, and is well tolerated. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-057
更新日期:2015-06-01 00:00:00
abstract::The Genomics of Drug Sensitivity in Cancer project recently added 4 years of additional data to a large-scale database designed to identify predictive biomarkers for cancer therapies. Freely available online, these data are driving research on the relationship between genomic features and drug responses to better tail...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2019-114
更新日期:2019-11-01 00:00:00
abstract::Oncogenes induce premature S phase, resulting in replication-transcription conflicts and replication stress. ...
journal_title:Cancer discovery
pub_type: 评论,新闻
doi:10.1158/2159-8290.CD-RW2018-039
更新日期:2018-04-01 00:00:00
abstract::A phase III trial of the agent MDV3100 in men with advanced prostate cancer previously treated with docetaxel-based chemotherapy is being stopped early so that the drug can be given to all participants. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB111711OL-09
更新日期:2011-12-01 00:00:00
abstract::The FDA granted accelerated approval to palbociclib for the treatment of estrogen receptor-positive, HER2-negative metastatic breast cancer in postmenopausal women who have not yet received endocrine-based therapy. Palbociclib is the first cell cycle-targeting CDK 4/6 inhibitor to reach the market. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-028
更新日期:2015-04-01 00:00:00
abstract::The clinical success of EGF receptor (EGFR) inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Two reports in this issue of Cancer Discovery uncover additional mechanisms by which EGFR-mutant lung cancers escape from EGFR kinase inhibitor treatment. These findings...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0387
更新日期:2012-10-01 00:00:00
abstract::The FDA approved 22 novel drugs in 2016, down from 45 in 2015. Four of the new therapies are for cancer treatment, and two are for cancer diagnosis. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-003
更新日期:2017-02-01 00:00:00
abstract::Researchers identified a small molecule that stimulates the production of stem cells in umbilical cord blood, potentially expanding treatment options for adults with hematologic cancers. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2014-153
更新日期:2014-12-01 00:00:00
abstract::Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alt...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-18-0275
更新日期:2018-09-01 00:00:00
abstract::A phase II study indicates that sacituzumab govitecan (IMMU-132), a Trop-2-specific antibody linked to the irinotecan metabolite SN-38, prolongs the progression-free survival of patients with advanced triple-negative breast cancer. IMMU-132 is well tolerated, causing fewer and more manageable side effects than irinote...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-162
更新日期:2016-01-01 00:00:00
abstract::Adding entinostat to exemestane improves survival in women with ER(+) advanced breast cancer. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2013-101
更新日期:2013-07-01 00:00:00
abstract::The IPRES signature is related to anti-PD-1 response, and high mutational load predicts survival. ...
journal_title:Cancer discovery
pub_type: 信件
doi:10.1158/2159-8290.CD-RW2016-057
更新日期:2016-05-01 00:00:00
abstract::A recent study suggests that complex genomic rearrangements in triple-negative breast cancer cells occur through a "Big Bang" model-early, short bursts of copy number aberrations, rather than progressive accumulation over time. Afterward, these aberrations are stably maintained in a handful of clones that expand to fo...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2016-110
更新日期:2016-10-01 00:00:00
abstract::Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2014-056
更新日期:2014-05-01 00:00:00
abstract::Adding a PI3K inhibitor to anti-estrogen receptor therapy may be a viable treatment option for women with advanced hormone receptor-positive breast cancer that becomes resistant to endocrine therapy, according to findings from the phase III BELLE-2 trial, presented at the 2015 San Antonio Breast Cancer Symposium. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-176
更新日期:2016-02-01 00:00:00
abstract::T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-20-0756
更新日期:2020-12-17 00:00:00