High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma

Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. There...

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Autores principales:	Laura Kohtamäki, Mariliina Arjama, Siru Mäkelä, Philipp Ianevski, Katja Välimäki, Susanna Juteau, Suvi Ilmonen, Daniela Ungureanu, Olli Kallioniemi, Astrid Murumägi, Micaela Hernberg
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Malignant melanoma Drug testing Kinase inhibitors Targeted therapy NRAS Personalized therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/eb0a34765eab4df0b6fe28e9b642ca47
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spelling	oai:doaj.org-article:eb0a34765eab4df0b6fe28e9b642ca472021-11-26T04:26:39ZHigh-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma1936-523310.1016/j.tranon.2021.101290https://doaj.org/article/eb0a34765eab4df0b6fe28e9b642ca472022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002813https://doaj.org/toc/1936-5233Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients’ cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.Laura KohtamäkiMariliina ArjamaSiru MäkeläPhilipp IanevskiKatja VälimäkiSusanna JuteauSuvi IlmonenDaniela UngureanuOlli KallioniemiAstrid MurumägiMicaela HernbergElsevierarticleMalignant melanomaDrug testingKinase inhibitorsTargeted therapyNRASPersonalized therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101290- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Malignant melanoma Drug testing Kinase inhibitors Targeted therapy NRAS Personalized therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Malignant melanoma Drug testing Kinase inhibitors Targeted therapy NRAS Personalized therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laura Kohtamäki Mariliina Arjama Siru Mäkelä Philipp Ianevski Katja Välimäki Susanna Juteau Suvi Ilmonen Daniela Ungureanu Olli Kallioniemi Astrid Murumägi Micaela Hernberg High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
description	Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients’ cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.
format	article
author	Laura Kohtamäki Mariliina Arjama Siru Mäkelä Philipp Ianevski Katja Välimäki Susanna Juteau Suvi Ilmonen Daniela Ungureanu Olli Kallioniemi Astrid Murumägi Micaela Hernberg
author_facet	Laura Kohtamäki Mariliina Arjama Siru Mäkelä Philipp Ianevski Katja Välimäki Susanna Juteau Suvi Ilmonen Daniela Ungureanu Olli Kallioniemi Astrid Murumägi Micaela Hernberg
author_sort	Laura Kohtamäki
title	High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
title_short	High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
title_full	High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
title_fullStr	High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
title_full_unstemmed	High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
title_sort	high-throughput ex vivo drug testing identifies potential drugs and drug combinations for nras-positive malignant melanoma
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/eb0a34765eab4df0b6fe28e9b642ca47
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High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma

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