Abstract:
:Therapeutics targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal-regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence-associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra-terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Lee HS,Lee S,Cho KHdoi
10.1002/ijc.33047subject
Has Abstractpub_date
2020-11-15 00:00:00pages
2824-2837issue
10eissn
0020-7136issn
1097-0215journal_volume
147pub_type
杂志文章abstract::A human cancer vaccine composed of autologous tumor cells modified with the hapten dinitrofluorobenzene (DNP) induces cell-mediated immunity to the tumor cells and the development of inflammatory responses within metastatic sites. In this study we determined whether DNP vaccine could induce regression of established m...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.1506.abs
更新日期:2001-11-01 00:00:00
abstract::Twenty-seven human colorectal adenocarcinomas were implanted s.c. into nude mice. A comparative study of chromosomes and DNA between fresh tumor (FT) and xenografted tumor cells (XT) could be performed in 9 cases. Losses or deletions were consistently found in FTs as well as in XTs, particularly on chromosomes 17 and/...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910440521
更新日期:1989-11-15 00:00:00
abstract::Our aim was to analyze the expression of the serine protease HtrA1 in human bladder tissue and urine in order to point out its possible association with the presence of urothelial bladder cancer. Bladder tissue and urine specimens from cancer patients with different tumor grades and stages (n = 68) and from individual...
journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:2013-12-01 00:00:00
abstract::Cancers of the stomach, pancreas, colon and rectum are increasingly regarded as being diet-influenced. Migrants to Australia from England, Scotland, Ireland, Poland, Yugoslavia, Greece, and Italy have come from countries with varied dietary backgrounds and gastrointestinal cancer risks. Age-standardized cancer death r...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910250402
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abstract::In an attempt to obtain cell lines from the different components found in primary breast cancers, we used a low-calcium medium to culture epithelial cells of mixed phenotype and a recombinant T antigen containing retrovirus to immortalize cells found in these cultures. In each case, the histology of the sample used fo...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910510417
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abstract::Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA...
journal_title:International journal of cancer
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更新日期:2020-08-15 00:00:00
abstract::Children are especially sensitive to ionizing radiation and chemical carcinogens, and limiting their cancer risk is of great public concern. Calorie restriction (CR) is a potent intervention for suppressing cancer. However, CR is generally not appropriate for children. This study, therefore, examined to see if adult-o...
journal_title:International journal of cancer
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更新日期:2014-09-01 00:00:00
abstract::CD4(+) Th cells that are restricted by MHC class II molecules play an important role in the induction of antitumor immune responses. We have established a stable CD4(+) Th cell clone (Th35-1A) from the PBMCs of a patient with primary cutaneous melanoma. The Th cell clone is noncytolytic and proliferates specifically i...
journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:2003-04-10 00:00:00
abstract::The mouse anti-id MAb MK2-23 bears the internal image of the antigenic determinant defined by anti-HMW-MAA MAb 763.74. Active specific immunotherapy with anti-id MAb MK2-23 is associated with a statistically significant prolongation of survival in patients with malignant melanoma. Characterization of the immune respon...
journal_title:International journal of cancer
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doi:10.1002/ijc.2910600310
更新日期:1995-01-27 00:00:00
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journal_title:International journal of cancer
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doi:10.1002/1097-0215(20001220)90:6<359::aid-ijc8>3.0.
更新日期:2000-12-20 00:00:00
abstract::In our previous experiments in Syrian hamsters the in vivo semiquantitative method of determination of the natural resistance-depressing (NRD) activity of tumor cells was described. It was demonstrated that inactivated cells of different tissue culture cell lines derived from in vivo tumors in contrast to normal, or i...
journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:1982-09-15 00:00:00
abstract::There are clear indications that inheritance plays an essential role in certain cases of human endometrial cancer, and there are at least 2 forms of early-onset heritable endometrial adenocarcinomas (EACs). Females of the BDII inbred rat strain are known to be genetically predisposed to endometrial carcinoma, and we h...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.1553
更新日期:2001-12-15 00:00:00
abstract::Medulloblastoma is a primitive neuroectodermal tumor of the cerebellum with poorly understood pathogenesis. Previous studies have reported loss of heterozygosity (LOH) on chromosome arms 17p, 11p and 9q and cytogenetic abnormalities of chromosome 1 in medulloblastoma. We have used the polymerase chain reaction to ampl...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/(SICI)1097-0215(19960703)67:1<11::AID-IJC3
更新日期:1996-07-03 00:00:00
abstract::Examination of the effect of the farnesylprotein transferase (FPTase) inhibitor UCF1-C/manumycin on NIH3T3 cells transfected with a normal N-ras gene and expressing high levels of the corresponding p21-ras protein showed that 10 microm UCF1-C immediately and reversibly inhibited growth in these cells, without modifyin...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/(sici)1097-0215(19980518)76:4<601::aid-ijc
更新日期:1998-05-18 00:00:00
abstract::Undifferentiated nasopharyngeal carcinoma (NPC) is a remarkable entity among human tumors because of its constant association with the Epstein-Barr virus (EBV). Malignant epithelial cells harbor the EBV genome and often express at least 2 species of latent EBV protein (EBNA1 and LMP1). Despite the massive presence of ...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910500605
更新日期:1992-04-01 00:00:00
abstract::In order to examine whether or not the expression of the apoptosis-related receptor Fas (CD-95/APO-1) and its ligand (FasL) has relevance for patient survival, immunohistochemistry was used to analyze the proteins of both factors in 164 non-small cell lung carcinomas. Patients with Fas-positive tumors exhibited signif...
journal_title:International journal of cancer
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更新日期:1999-06-21 00:00:00
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journal_title:International journal of cancer
pub_type: 临床试验,杂志文章
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更新日期:1999-04-12 00:00:00
abstract::Primary cultures derived from pre-cancerous and cancerous human colon tissue are essential for understanding normal and abnormal growth function in the large intestine. Here presented are (i) the methodology for routine establishment of primary cultures of normal, adenoma- and carcinoma-derived cells, and (ii) data fo...
journal_title:International journal of cancer
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更新日期:1998-01-30 00:00:00
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journal_title:International journal of cancer
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journal_title:International journal of cancer
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journal_title:International journal of cancer
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abstract::It is unclear which chromosome arms frequently show loss of heterozygosity (LOH) in adenocarcinoma of the uterine cervix. To identify such chromosomal arms, LOH on 52 different chromosome loci was examined using laser capture microdissection and PCR-LOH analysis in 25 common-type adenocarcinomas, comprising 13 cases o...
journal_title:International journal of cancer
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abstract::LAF-4, which encodes a nuclear protein with transactivation potential, is fused to the MLL gene in acute lymphoblastic leukemia (ALL). We identified LAF-4 as a gene that is transcriptionally deregulated in breast tumors and thus may have a pathological role in mammary tumorigenesis. In line with the previous finding t...
journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:2005-07-01 00:00:00
abstract::Multiple myeloma (MM) is a B lymphocyte malignancy that remains incurable despite extensive research efforts. This is due, in part, to frequent disease recurrences associated with the persistence of myeloma cancer stem cells (mCSCs). Bone marrow mesenchymal stromal cells (BMSCs) play critical roles in supporting mCSCs...
journal_title:International journal of cancer
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journal_title:International journal of cancer
pub_type: 杂志文章
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更新日期:1996-02-08 00:00:00
abstract::Spleen cells from BALB/c mice bearing syngeneic, methylcholanthrene-induced sarcomas were cultured in vitro. In agreement with previous observations, two tumor-specific activities could be demonstrated in the culture supernatants: the supernatants suppressed (blocked) specific lymph-node cell-mediated cytotoxicity dir...
journal_title:International journal of cancer
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更新日期:1975-10-15 00:00:00
abstract::The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population-based Finnish register data. All women with the diagnosis of LP (n = 13,100) were identified from the Finnish Hospital Discharge Registry from 1969-2012. These patients were linked with sub...
journal_title:International journal of cancer
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abstract::Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mamm...
journal_title:International journal of cancer
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更新日期:1996-09-17 00:00:00
abstract::Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon canc...
journal_title:International journal of cancer
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2019-07-15 00:00:00
abstract::The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the "molecular switch" model, postulates that CIN3 can evolve directly from ...
journal_title:International journal of cancer
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更新日期:2018-10-01 00:00:00