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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2018 |
| Country: | España |
| Institution: | Universidad de Cantabria (UC) |
| Repository: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Language: | English |
| OAI Identifier: | oai:repositorio.unican.es:10902/15278 |
| Online Access: | http://hdl.handle.net/10902/15278 |
| Access Level: | Open access |
| Keyword: | Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| _version_ | 1878741307201945600 |
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| author | Llerena Santiago, Susana |
| 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 |
| author_browse | Agraz Doblas, Antonio Manuel Agüero Balbín, Jesús Almaraz, Carmen Arias Loste, María Teresa Cagigas Fernández, Carmen|||0000-0002-1675-5120 Castillo Suescun, Federico José Cereceda, Laura Crespo Facorro, Benedicto|||0000-0001-9709-1276 Crespo García, Javier Curiel Del Olmo, Soraya García Blanco, Agustín García Díaz, Nuria Isidro, Pablo Llerena Santiago, Susana Llorca Díaz, Francisco Javier|||0000-0001-8569-861X López Hoyos, Marcos López López, Carlos|||0000-0002-8901-741X Martín Ramos, Luis Martínez, Nerea Piris, Miguel Ángel Pisonero Fraga, Helena Puente, Ángela Rodríguez de Lope López, Carlos Santibáñez Margüello, Miguel|||0000-0003-2634-615X Vaqué Díez, José Pedro|||0000-0002-3913-2495 Varela Egocheaga, Ignacio|||0000-0002-0969-506X Varela, María |
| 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 |
| collection | UCrea Repositorio Abierto de la Universidad de Cantabria |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_e2d7b919af2f3713d8a2c2d1b9e71f7d |
| institution | Universidad de Cantabria (UC) |
| instname_str | Universidad de Cantabria (UC) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositorio.unican.es:10902/15278 |
| publishDate | 2018 |
| publishDateSort | 2018 |
| publisher | Impact Journals |
| publisherStr | Impact Journals |
| reponame_str | UCrea Repositorio Abierto de la Universidad de Cantabria |
| spelling | Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR 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 Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy 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 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 Journals http://hdl.handle.net/10902/15278 |
| 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 | 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_short | 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 |
| topic | Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| topic_facet | Hepatocellular Carcinoma Mutations Sorafenib Targeted Therapy AKT/mTOR |
| url | http://hdl.handle.net/10902/15278 |