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

• Published in: Translational oncology 2022-01, Vol.15 (1), p.101290-101290, Article 101290
• Main Authors: Kohtamäki, Laura, Arjama, Mariliina, Mäkelä, Siru, Ianevski, Philipp, Välimäki, Katja, Juteau, Susanna, Ilmonen, Suvi, Ungureanu, Daniela, Kallioniemi, Olli, Murumägi, Astrid, Hernberg, Micaela
• Format: Article
• Language: English
• Subjects: Drug testing; Kinase inhibitors; Malignant melanoma; NRAS; Original Research; Personalized therapy; Targeted therapy
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2021.101290

•We established patient-derived cancer cell (PDC) lines from NRAS-positive MM tumors.•We carried out high-throughput drug testing with PDCs against 527 oncology drugs.•PDCs were sensitive to PI3K, mTOR, PLK1, MEK, ERK, and RAF inhibitors.•Drug combination synergies were identified.•Our results support application of PDCs for functional drug testing. 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.