1.Pathologic diagnosis of colorectal cancer in the era of personalized therapy.
Chinese Journal of Pathology 2014;43(2):73-76
Antineoplastic Agents
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therapeutic use
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Colorectal Neoplasms
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classification
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drug therapy
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genetics
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pathology
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Humans
;
Microsatellite Instability
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Mutation
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Polymorphism, Single Nucleotide
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Precision Medicine
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Proto-Oncogene Proteins
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genetics
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Proto-Oncogene Proteins B-raf
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genetics
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Proto-Oncogene Proteins p21(ras)
;
ras Proteins
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genetics
2.The efficacy and side effects of rigosertib combined with chemotherapy in KRAS mutant colorectal cancer mice.
Hao Chen ZHANG ; Xin Yi ZHOU ; Dong Liang FU ; Yu Wei DING ; Qian XIAO ; Ying YUAN
Chinese Journal of Oncology 2023;45(2):138-145
Objective: To investigate the effect of rigosertib (RGS) combined with classic chemotherapy drugs including 5-fluorouracil, oxaliplatin, and irinotecan in colorectal cancer. Methods: Explore the synergy effects of RGS and 5-fluorouracil (5-FU), oxaliplatin (OXA), and irinotecan (IRI) on colorectal cancer by subcutaneously transplanted tumor models of mice. The mice were randomly divided into control group, RGS group, 5-FU group, OXA group, IRI group, 5-FU+ RGS group, OXA+ RGS group and IRI+ RGS group. The synergy effects of RGS and OXA on KRAS mutant colorectal cancer cell lines in vitro was detected by CCK-8. Ki-67 immunohistochemistry and TdT-mediated dUTP nick-end labeling (TUNEL) staining were performed on the mouse tumor tissue sections, and the extracted tumor tissue was analyzed by western blot. The blood samples of mice after chemotherapy and RGS treatment were collected, blood routine and liver and kidney function analysis were conducted, and H&E staining on liver sections was performed to observe the side effects of chemotherapy and RGS. Results: The subcutaneously transplanted tumor models were established successfully in all groups. 55 days after administration, the fold change of tumor size of OXA+ RGS group was 37.019±8.634, which is significantly smaller than 77.571±15.387 of RGS group (P=0.029) and 92.500±13.279 of OXA group (P=0.008). Immunohistochemical staining showed that the Ki-67 index of tumor tissue in control group, OXA group, RGS group and OXA+ RGS group were (100.0±16.8)%, (35.6±11.3)%, (54.5±18.1)% and (15.4±3.9)%, respectively. The Ki-67 index of OXA+ RGS group was significantly lower than that in control group (P=0.014), but there was no significant difference compared to OXA group and RGS group (OXA: P=0.549; RGS: P=0.218). TUNEL fluorescence staining showed that the apoptotic level of OXA+ RGS group was 3.878±0.547, which was significantly higher than 1.515±0.442 of OXA group (P=0.005) and 1.966±0.261 of RGS group (P=0.008). Western blot showed that the expressions of apoptosis related proteins such as cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 8 in the tumor tissues of mice in the OXA+ RGS group were higher than those in control group, OXA group and RGS group. After the mice received RGS combined with chemotherapy drugs, there was no significant effect on liver and kidney function indexes, but the combined use of oxaliplatin and RGS significantly reduced the white blood cells [(0.385±0.215)×10(9)/L vs (5.598±0.605)×10(9)/L, P<0.001] and hemoglobin[(56.000±24.000)g/L vs (153.333±2.231)g/L, P=0.001] of the mice. RGS, chemotherapy combined with RGS and chemotherapy alone did not significantly increase the damage to liver cells. Conclusions: The combination of RGS and oxaliplatin has a stronger anti-tumor effect on KRAS mutant colorectal cancer. RGS single agent will not cause significant bone marrow suppression and hepatorenal injury in mice, but its side effects may increase correspondingly after combined with chemotherapy.
Animals
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Mice
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Antineoplastic Combined Chemotherapy Protocols
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Apoptosis Regulatory Proteins
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Colorectal Neoplasms/genetics*
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Fluorouracil/pharmacology*
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Irinotecan/therapeutic use*
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Ki-67 Antigen
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Oxaliplatin
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Proto-Oncogene Proteins p21(ras)/therapeutic use*
3.Current status and outlook of medical treatment for KRAS-mutated non-small cell lung cancer.
Wei XU ; Xiao Li ZHUO ; Lei LIU ; Jing ZHAO ; Xiao Yan LIN ; Guo Bin FU
Chinese Journal of Oncology 2023;45(2):111-116
Lung cancer remains the leading cause of cancer-related deaths in men and women worldwide, and 85% of these patients have non-small cell lung cancer. In recent years, the clinical use of targeted drug therapy and immune checkpoint inhibitors has dramatically changed the treatment landscape for advanced NSCLC. The mechanism and the value of targeted therapies have been a hot topic of research, as KRAS is one of the earliest discovered and most frequently mutated oncogenes, which is activated by binding to GTP and triggers a series of cascade reactions in cell proliferation and mitosis. The KRAS protein acts as a molecular switch and is activated by binding to GTP, triggering a series of cascade responses in cell proliferation and mitosis. Clinically, patients with KRAS mutated NSCLC have poor response to systemic medical therapy and poor prognosis. Since the first report of KRAS gene in 1982, research on KRAS targeted therapeutics has been slow, and previous studies such as farnesyltransferase inhibitors and downstream protein inhibitors of KRAS signaling pathway have not achieved the expected results, making KRAS long defined as a "non-druggable target". The deeper understanding of the crystal structure of KRAS has led to the discovery of potential therapeutic sites for KRAS and the development of several drugs directly targeting KRAS, especially KRAS G12C inhibitors such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have shown encouraging results in clinical trials. In recent years, studies on the therapeutic efficacy of immune checkpoint inhibitors for KRAS-mutated NSCLC have made some progress. In this review, we systematically introduce the basic understanding of RAS gene and clinical characteristics of KRAS mutated NSCLC patients, summarize the medical treatments for KRAS mutated NSCLC, including chemotherapy, anti-vascular drug therapy and tumor immunotherapy, and focus on the review and outlook of the research progress of KRAS targeted therapy.
Male
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Humans
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Female
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Carcinoma, Non-Small-Cell Lung/pathology*
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Lung Neoplasms/genetics*
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Proto-Oncogene Proteins p21(ras)/therapeutic use*
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Genes, ras
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Immune Checkpoint Inhibitors/therapeutic use*
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Guanosine Triphosphate/therapeutic use*
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Mutation
4.Research Progress of Proteolysis Targeting Chimeria in NSCLC Therapy.
Lin JIANG ; Jingbo ZHANG ; Jiaqi HU ; Haixiang QI ; Heng XU
Chinese Journal of Lung Cancer 2022;25(7):477-481
Proteolysis targeting chimeria (PROTAC) degrades target proteins by utilizing the ubiquitin-proteasome pathway, subverting the concept of traditional small molecule inhibitors. Among the common mutation targets of non-small cell lung cancer (NSCLC), PROTAC technology has successfully achieved the effective degradation of kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK ) and other proteins in preclinical studies. PROTAC drugs with their unique event-driven advantages, are expected to overcome acquired drug resistance caused by small molecule inhibitors and show good therapeutic potential for undruggable targets, thereby providing a new strategy for the treatment of NSCLC.
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Carcinoma, Non-Small-Cell Lung/pathology*
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Humans
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Lung Neoplasms/pathology*
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Mutation
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Protein Kinase Inhibitors/therapeutic use*
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Proteolysis
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Proto-Oncogene Proteins p21(ras)/genetics*
5.A Case Report of Advanced Lung Adenocarcinoma Harboring KRAS Mutation Treated with Anlotinib.
Yudong SU ; Zhaoting MENG ; Xiaoyan XU ; XinYue WANG ; Ran ZUO ; Yunxia HOU ; Kai LI ; Peng CHEN
Chinese Journal of Lung Cancer 2018;21(5):428-430
In recent years, the number of advanced non-small cell lung cancer (NSCLC) patients has gradually increased, and the treatment methods have also been significantly increased. However, there are no standard treatment plans at home and abroad for third-line and above patients who are refractory to targeted therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) or chemotherapy. The clinical treatment effect is also not satisfactory. Anlotinib is a novel TKI targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit. ALTER0303 trail, phase III study has demonstrated that Anlotinib significantly prolonged overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients as 3rd line treatment.Here we report a case of advanced lung adenocarcinoma harboring KRAS mutation treated with Anlotinib.
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Adenocarcinoma
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drug therapy
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enzymology
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genetics
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pathology
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Adenocarcinoma of Lung
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Aged
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Antineoplastic Agents
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therapeutic use
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Humans
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Indoles
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therapeutic use
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Lung Neoplasms
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drug therapy
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enzymology
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genetics
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pathology
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Male
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Mutation
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Proto-Oncogene Proteins p21(ras)
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genetics
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metabolism
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Quinolines
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therapeutic use
6.Effect of KRAS mutation on efficacy of Cetuximab combined with chemotherapy in advanced colorectal cancer patients.
Xing-xiang PU ; Yan-hong DENG ; Fei XU ; Jian XIAO ; Hong-qiang GUO ; He HUANG ; Ying TIAN ; You-jian HE ; Tong-yu LIN
Chinese Journal of Gastrointestinal Surgery 2009;12(6):594-597
OBJECTIVETo explore the relationship between KRAS gene status and efficacy of Cetuximab (C225) combined with chemotherapy on advanced colorectal cancer in Chinese patients, and to evaluate the safety of C225.
METHODSFrom May 2006 to March 2009, 81 patients with advanced colorectal cancer received Cetuximab combined with chemotherapy were enrolled in this study. The rate of KRAS mutation and the relationship of KRAS with response rate (RR), progression-free survivor (PFS), overall survival (OS) and adverse reaction of C225 were analyzed retrospectively.
RESULTSAll the 81 patients received C225 therapy, and the overall RR was 33.3%. The RR of initiate therapy was 57.1%; of the second line and over the third line therapy was 38.5% and 22.0% respectively. KRAS gene phenotype examination was performed in 44 patients whose tumor samples were available. KRAS mutation was found in 20 cases (45%). Out of 44 patients, 43 were evaluable for response. RR was 5% and 43.48% in KRAS mutation and wild KRAS patients respectively (P =0.002). The median PFS was 7.0 weeks and 18.6 weeks in mutational KRAS patients and wild KRAS patients, reaching statistical significance (P =0.003). The median OS was 15.2 months and 17.3 months in mutational KRAS patients and wild KRAS patients respectively without statistical significance (P =0.463). The common adverse reactions were leucopenia, nausea, vomiting and rash. All the adverse reactions were tolerated. The incidence of skin rash in patients with mutational KRAS and patients without KRAS mutation was 40% and 42% respectively, without statistical significance (P =0.91).
CONCLUSIONC225 combined with chemotherapy is well-tolerated in Chinese patients with advanced colorectal cancer, and it can significantly prolong PFS of patients with wild KRAS as compared to patients with KRAS mutation.
Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cetuximab ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Prognosis ; Proto-Oncogene Proteins ; genetics ; Proto-Oncogene Proteins p21(ras) ; Retrospective Studies ; ras Proteins ; genetics
7.USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer.
Dexin YANG ; Yuqin FENG ; Haohua LU ; Kelie CHEN ; Jinming XU ; Peiwei LI ; Tianru WANG ; Dajing XIA ; Yihua WU
Journal of Zhejiang University. Science. B 2023;24(2):143-156
This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‒1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‒2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‒1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‒1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‒0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‒0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‒8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‒6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
Humans
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Carcinoma, Non-Small-Cell Lung/genetics*
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ErbB Receptors/genetics*
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Extracellular Matrix Proteins/genetics*
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Immune Checkpoint Inhibitors/therapeutic use*
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Lung Neoplasms/genetics*
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Mutation
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Protein Kinase Inhibitors/therapeutic use*
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Proto-Oncogene Proteins p21(ras)/genetics*
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Treatment Outcome
8.Progress of targeted therapy related to K-ras mutation.
Chinese Journal of Pathology 2012;41(1):59-61
Antineoplastic Agents
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therapeutic use
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Colorectal Neoplasms
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drug therapy
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genetics
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metabolism
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Genes, ras
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genetics
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Humans
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Lung Neoplasms
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drug therapy
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genetics
;
metabolism
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Molecular Targeted Therapy
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methods
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Mutation
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Neoplasms
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drug therapy
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genetics
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metabolism
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Pancreatic Neoplasms
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drug therapy
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genetics
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metabolism
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Proto-Oncogene Proteins
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genetics
;
metabolism
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Proto-Oncogene Proteins p21(ras)
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Receptor, Epidermal Growth Factor
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drug effects
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metabolism
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Signal Transduction
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ras Proteins
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genetics
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metabolism
9.Issues related to basic research on uterine and ovarian tumor pathology.
Chinese Journal of Pathology 2007;36(8):508-510
Antibodies, Monoclonal
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therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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therapeutic use
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Boronic Acids
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therapeutic use
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Bortezomib
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Cervical Intraepithelial Neoplasia
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pathology
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Female
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Human papillomavirus 16
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isolation & purification
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Humans
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Ovarian Neoplasms
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drug therapy
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metabolism
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pathology
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Papillomavirus Infections
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Proto-Oncogene Proteins
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metabolism
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Proto-Oncogene Proteins B-raf
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metabolism
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Proto-Oncogene Proteins p21(ras)
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Pyrazines
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therapeutic use
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Trastuzumab
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Tumor Suppressor Protein p53
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metabolism
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Uterine Cervical Neoplasms
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drug therapy
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pathology
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virology
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ras Proteins
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metabolism
10.Impact of genetic alterations on mTOR-targeted cancer therapy.
Chinese Journal of Cancer 2013;32(5):270-274
Rapamycin and its derivatives (rapalogs), a group of allosteric inhibitors of mammalian target of rapamycin (mTOR), have been actively tested in a variety of cancer clinical trials, and some have been approved by the Food and Drug Administration for the treatment of certain types of cancers. However, the single agent activity of these compounds in many tumor types remains modest. The mTOR axis is regulated by multiple upstream signaling pathways. Because the genes (e.g., PIK3CA, KRAS, PTEN, and LKB1) that encode key components in these signaling pathways are frequently mutated in human cancers, a subset of cancer types may be addicted to a given mutation, leading to hyperactivation of the mTOR axis. Thus, efforts have been made to demonstrate the potential impact of genetic alterations on rapalog-based or mTOR-targeted cancer therapy. This review will primarily summarize research advances in this direction.
Antibiotics, Antineoplastic
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therapeutic use
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Cell Line, Tumor
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Class I Phosphatidylinositol 3-Kinases
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Humans
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Mutation
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Neoplasms
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drug therapy
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metabolism
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PTEN Phosphohydrolase
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genetics
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metabolism
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Phosphatidylinositol 3-Kinases
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genetics
;
metabolism
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Protein-Serine-Threonine Kinases
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genetics
;
metabolism
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Proto-Oncogene Proteins
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genetics
;
metabolism
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Proto-Oncogene Proteins p21(ras)
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Signal Transduction
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Sirolimus
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analogs & derivatives
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therapeutic use
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TOR Serine-Threonine Kinases
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antagonists & inhibitors
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metabolism
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ras Proteins
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genetics
;
metabolism