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A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

ZHAO CHEN ; CHENG, Katherine ; PENG GAO ; WOO, Michele S ; CHUNXIAO XU ; YANAGITA, Masahiko ; ALTABEF, Abigail ; SHUMEIWANG ; LEE, Charles ; NAKADA, Yuji ; PENA, ChristopherG ; YANPINGSUN ; WALTON, Zandra ; FRANCHETTI, Yoko ; YAO, Catherine ; SAUR, Amy ; CAMERON, Michael D ; NISHINO, Mizuki ; NEIL HAYES, D ; WILKERSON, Matthew D ; ROBERTS, Patrick J ; LEE, Carrie B ; BARDEESY, Nabeel ; WANGA, Yuchuan ; BUTANEY, Mohit ; CHIRIEAC, Lucian R ; COSTA, Daniel B ; JACKMAN, David ; SHARPLESS, Norman E ; CASTRILLON, Diego H ; DEMETRI, George D ; JÄNNE, Pasi A ; PAOLO PANDOLFI, Pier ; CANTLEY, Lewis C ; EBI, Hiromichi ; KUNG, Andrew L ; ENGELMAN, Jeffrey A ; WONG, Kwok-Kin ; SHIMAMURA, Takeshi ; YAN LIU ; TUPPER, Tanya ; JING OUYANG ; JIE LI

Nature (London), 2012-03, Vol.483 (7391), p.613-617 [Periódico revisado por pares]

London: Nature Publishing Group

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Título:
A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Autor: ZHAO CHEN ; CHENG, Katherine ; PENG GAO ; WOO, Michele S ; CHUNXIAO XU ; YANAGITA, Masahiko ; ALTABEF, Abigail ; SHUMEIWANG ; LEE, Charles ; NAKADA, Yuji ; PENA, ChristopherG ; YANPINGSUN ; WALTON, Zandra ; FRANCHETTI, Yoko ; YAO, Catherine ; SAUR, Amy ; CAMERON, Michael D ; NISHINO, Mizuki ; NEIL HAYES, D ; WILKERSON, Matthew D ; ROBERTS, Patrick J ; LEE, Carrie B ; BARDEESY, Nabeel ; WANGA, Yuchuan ; BUTANEY, Mohit ; CHIRIEAC, Lucian R ; COSTA, Daniel B ; JACKMAN, David ; SHARPLESS, Norman E ; CASTRILLON, Diego H ; DEMETRI, George D ; JÄNNE, Pasi A ; PAOLO PANDOLFI, Pier ; CANTLEY, Lewis C ; EBI, Hiromichi ; KUNG, Andrew L ; ENGELMAN, Jeffrey A ; WONG, Kwok-Kin ; SHIMAMURA, Takeshi ; YAN LIU ; TUPPER, Tanya ; JING OUYANG ; JIE LI
Assuntos: Animal tumors. Experimental tumors ; Animals ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis ; Benzimidazoles - pharmacology ; Benzimidazoles - therapeutic use ; Biological and medical sciences ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cancer therapies ; Chemotherapy ; Clinical trials ; Clinical Trials, Phase II as Topic ; Confidence intervals ; Disease Models, Animal ; Dosage and administration ; Drug dosages ; Drug Evaluation, Preclinical ; Drug therapy ; Experimental respiratory system tumors ; Fluorodeoxyglucose F18 ; Gene mutations ; Genes, p53 - genetics ; Genetic aspects ; Health aspects ; Humans ; Hypotheses ; Lung cancer ; Lung cancer, Non-small cell ; Lung Neoplasms - drug therapy ; Lung Neoplasms - enzymology ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; MAP Kinase Signaling System - drug effects ; Medical sciences ; Mice ; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors ; Mutation ; Mutation - genetics ; Patients ; Pharmaceutical industry ; Pharmacogenetics - methods ; Pharmacology. Drug treatments ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases - deficiency ; Protein-Serine-Threonine Kinases - genetics ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; Randomized Controlled Trials as Topic ; ras Proteins - genetics ; ras Proteins - metabolism ; Reproducibility of Results ; Taxoids - therapeutic use ; Tomography ; Tomography, X-Ray Computed ; Treatment Outcome ; Tumors
É parte de: Nature (London), 2012-03, Vol.483 (7391), p.613-617
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
Editor: London: Nature Publishing Group
Idioma: Inglês

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A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

London: Nature Publishing Group

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