HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors
IntroductionNeuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require approp...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.1045038/full |
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| author | Chiara Liverani Chiara Spadazzi Toni Ibrahim Federica Pieri Flavia Foca Chiara Calabrese Alessandro De Vita Giacomo Miserocchi Claudia Cocchi Silvia Vanni Giorgio Ercolani Davide Cavaliere Nicoletta Ranallo Elisa Chiadini Giovanna Prisinzano Stefano Severi Maddalena Sansovini Giovanni Martinelli Alberto Bongiovanni Laura Mercatali |
| author_facet | Chiara Liverani Chiara Spadazzi Toni Ibrahim Federica Pieri Flavia Foca Chiara Calabrese Alessandro De Vita Giacomo Miserocchi Claudia Cocchi Silvia Vanni Giorgio Ercolani Davide Cavaliere Nicoletta Ranallo Elisa Chiadini Giovanna Prisinzano Stefano Severi Maddalena Sansovini Giovanni Martinelli Alberto Bongiovanni Laura Mercatali |
| author_sort | Chiara Liverani |
| collection | DOAJ |
| description | IntroductionNeuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted.MethodsWe investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.ResultsLenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.DiscussionLenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome. |
| first_indexed | 2024-04-10T21:20:40Z |
| format | Article |
| id | doaj.art-6702750d458546d594d1121a5c66b84f |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-10T21:20:40Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-6702750d458546d594d1121a5c66b84f2023-01-20T06:11:22ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-01-011310.3389/fendo.2022.10450381045038HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumorsChiara Liverani0Chiara Spadazzi1Toni Ibrahim2Federica Pieri3Flavia Foca4Chiara Calabrese5Alessandro De Vita6Giacomo Miserocchi7Claudia Cocchi8Silvia Vanni9Giorgio Ercolani10Davide Cavaliere11Nicoletta Ranallo12Elisa Chiadini13Giovanna Prisinzano14Stefano Severi15Maddalena Sansovini16Giovanni Martinelli17Alberto Bongiovanni18Laura Mercatali19Bioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyOsteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, ItalyPathology Unit, “Morgagni-Pierantoni” Hospital, Forlì, ItalyUnit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyGeneral and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, Forlì, ItalyGeneral and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, Forlì, ItalyOsteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyUnit of Nuclear Medicine, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyUnit of Nuclear Medicine, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyScientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyOsteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyBioscience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, ItalyIntroductionNeuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted.MethodsWe investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.ResultsLenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.DiscussionLenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.https://www.frontiersin.org/articles/10.3389/fendo.2022.1045038/fullnenprimary culturesLenvatinib efficacyHRAS overexpressionpredictive marker |
| spellingShingle | Chiara Liverani Chiara Spadazzi Toni Ibrahim Federica Pieri Flavia Foca Chiara Calabrese Alessandro De Vita Giacomo Miserocchi Claudia Cocchi Silvia Vanni Giorgio Ercolani Davide Cavaliere Nicoletta Ranallo Elisa Chiadini Giovanna Prisinzano Stefano Severi Maddalena Sansovini Giovanni Martinelli Alberto Bongiovanni Laura Mercatali HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors Frontiers in Endocrinology nen primary cultures Lenvatinib efficacy HRAS overexpression predictive marker |
| title | HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| title_full | HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| title_fullStr | HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| title_full_unstemmed | HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| title_short | HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| title_sort | hras overexpression predicts response to lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors |
| topic | nen primary cultures Lenvatinib efficacy HRAS overexpression predictive marker |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.1045038/full |
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