Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Universidad de Cantabria (UC) |
| Repositorio: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.unican.es:10902/15278 |
| Acceso en línea: | http://hdl.handle.net/10902/15278 |
| Access Level: | acceso abierto |
| Palabra clave: | Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
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Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTORLlerena Santiago, SusanaGarcía Díaz, NuriaCuriel Del Olmo, SorayaAgraz Doblas, Antonio ManuelGarcía Blanco, AgustínPisonero Fraga, HelenaVarela, MaríaSantibáñez Margüello, Miguel|||0000-0003-2634-615XAlmaraz, CarmenCereceda, LauraMartínez, NereaArias Loste, María TeresaPuente, ÁngelaMartín Ramos, LuisRodríguez de Lope López, CarlosCastillo Suescun, Federico JoséCagigas Fernández, Carmen|||0000-0002-1675-5120Isidro, PabloLópez López, Carlos|||0000-0002-8901-741XLópez Hoyos, MarcosLlorca Díaz, Francisco Javier|||0000-0001-8569-861XAgüero Balbín, JesúsCrespo Facorro, Benedicto|||0000-0001-9709-1276Varela Egocheaga, Ignacio|||0000-0002-0969-506XPiris, Miguel ÁngelCrespo García, JavierVaqué Díez, José Pedro|||0000-0002-3913-2495Hepatocellular CarcinomaMutationsSorafenibTargeted TherapyAKT/mTORHepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.FUNDING: Grants from ISCIII, co-financed by the European Union (FEDER) (PI16/00156), Ramón and Cajal research program from MINECO (RYC-2013-14097) and FUNDACIÓN LUCHAMOS POR LA VIDA to JPV. Grants from ISCIII (RD06/0020/0107-RD012/0036/0060) to MAP. Grant from ISCIII (Ref. PIE15/00079) to JC & JPV. NGD is a recipient of a UC-IDIVAL pre-doctoral fellow. I.V. was also supported by the Ramón and Cajal research program.Impact JournalsUniversidad de Cantabria20182018-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/15278Oncotarget. 2018 Jul 20;9(56):30869-30882reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/152782026-06-02T12:39:31Z |
| dc.title.none.fl_str_mv |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| title |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| spellingShingle |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR Llerena Santiago, Susana Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| title_short |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| title_full |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| title_fullStr |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| title_full_unstemmed |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| title_sort |
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR |
| dc.creator.none.fl_str_mv |
Llerena Santiago, Susana García Díaz, Nuria Curiel Del Olmo, Soraya Agraz Doblas, Antonio Manuel García Blanco, Agustín Pisonero Fraga, Helena Varela, María Santibáñez Margüello, Miguel|||0000-0003-2634-615X Almaraz, Carmen Cereceda, Laura Martínez, Nerea Arias Loste, María Teresa Puente, Ángela Martín Ramos, Luis Rodríguez de Lope López, Carlos Castillo Suescun, Federico José Cagigas Fernández, Carmen|||0000-0002-1675-5120 Isidro, Pablo López López, Carlos|||0000-0002-8901-741X López Hoyos, Marcos Llorca Díaz, Francisco Javier|||0000-0001-8569-861X Agüero Balbín, Jesús Crespo Facorro, Benedicto|||0000-0001-9709-1276 Varela Egocheaga, Ignacio|||0000-0002-0969-506X Piris, Miguel Ángel Crespo García, Javier Vaqué Díez, José Pedro|||0000-0002-3913-2495 |
| author |
Llerena Santiago, Susana |
| author_facet |
Llerena Santiago, Susana García Díaz, Nuria Curiel Del Olmo, Soraya Agraz Doblas, Antonio Manuel García Blanco, Agustín Pisonero Fraga, Helena Varela, María Santibáñez Margüello, Miguel|||0000-0003-2634-615X Almaraz, Carmen Cereceda, Laura Martínez, Nerea Arias Loste, María Teresa Puente, Ángela Martín Ramos, Luis Rodríguez de Lope López, Carlos Castillo Suescun, Federico José Cagigas Fernández, Carmen|||0000-0002-1675-5120 Isidro, Pablo López López, Carlos|||0000-0002-8901-741X López Hoyos, Marcos Llorca Díaz, Francisco Javier|||0000-0001-8569-861X Agüero Balbín, Jesús Crespo Facorro, Benedicto|||0000-0001-9709-1276 Varela Egocheaga, Ignacio|||0000-0002-0969-506X Piris, Miguel Ángel Crespo García, Javier Vaqué Díez, José Pedro|||0000-0002-3913-2495 |
| author_role |
author |
| author2 |
García Díaz, Nuria Curiel Del Olmo, Soraya Agraz Doblas, Antonio Manuel García Blanco, Agustín Pisonero Fraga, Helena Varela, María Santibáñez Margüello, Miguel|||0000-0003-2634-615X Almaraz, Carmen Cereceda, Laura Martínez, Nerea Arias Loste, María Teresa Puente, Ángela Martín Ramos, Luis Rodríguez de Lope López, Carlos Castillo Suescun, Federico José Cagigas Fernández, Carmen|||0000-0002-1675-5120 Isidro, Pablo López López, Carlos|||0000-0002-8901-741X López Hoyos, Marcos Llorca Díaz, Francisco Javier|||0000-0001-8569-861X Agüero Balbín, Jesús Crespo Facorro, Benedicto|||0000-0001-9709-1276 Varela Egocheaga, Ignacio|||0000-0002-0969-506X Piris, Miguel Ángel Crespo García, Javier Vaqué Díez, José Pedro|||0000-0002-3913-2495 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad de Cantabria |
| dc.subject.none.fl_str_mv |
Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| topic |
Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| description |
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms. |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2018-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 NA http://purl.org/coar/version/c_be7fb7dd8ff6fe43 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10902/15278 |
| url |
http://hdl.handle.net/10902/15278 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Impact Journals |
| publisher.none.fl_str_mv |
Impact Journals |
| dc.source.none.fl_str_mv |
Oncotarget. 2018 Jul 20;9(56):30869-30882 reponame:UCrea Repositorio Abierto de la Universidad de Cantabria instname:Universidad de Cantabria (UC) |
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Universidad de Cantabria (UC) |
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UCrea Repositorio Abierto de la Universidad de Cantabria |
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UCrea Repositorio Abierto de la Universidad de Cantabria |
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1869422447694970880 |
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15,300724 |