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

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Kohtamäki , L , Arjama , M , Mäkelä , S , Ianevski , P , Välimäki , K , Juteau , S , Ilmonen , S , Ungureanu , D , Kallioniemi , O , Murumägi , A & Hernberg , M 2022 , ' High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma ' , Translational oncology , vol. 15 , no. 1 , 101290 . https://doi.org/10.1016/j.tranon.2021.101290

Title: High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma
Author: Kohtamäki, Laura; Arjama, Mariliina; Mäkelä, Siru; Ianevski, Philipp; Välimäki, Katja; Juteau, Susanna; Ilmonen, Suvi; Ungureanu, Daniela; Kallioniemi, Olli; Murumägi, Astrid; Hernberg, Micaela
Contributor organization: HUS Comprehensive Cancer Center
Department of Oncology
University of Helsinki
Institute for Molecular Medicine Finland
Precision Systems Medicine
HUSLAB
Department of Pathology
HUS Musculoskeletal and Plastic Surgery
Clinicum
Department of Surgery
ATG - Applied Tumor Genomics
Research Programs Unit
Date: 2022-01
Language: eng
Number of pages: 11
Belongs to series: Translational oncology
ISSN: 1936-5233
DOI: https://doi.org/10.1016/j.tranon.2021.101290
URI: http://hdl.handle.net/10138/343682
Abstract: 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.
Subject: Malignant melanoma
Drug testing
Kinase inhibitors
Targeted therapy
NRAS
Personalized therapy
PI3K INHIBITOR GDC-0941
MUTANT MELANOMA
MEK INHIBITION
COMBINED BRAF
DOUBLE-BLIND
SENSITIVITY
MUTATIONS
KIT
MULTICENTER
DABRAFENIB
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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