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Background: Transcriptional plasticity can underly treatment resistance in cancer whereby cells rewire their circuitry to evade the activity of targeted drugs. This has been shown in the case of ALK-positive anaplastic large cell lymphoma (ALCL) treated with ALK inhibitors whereby bypass resistance mechanisms have been identified1,2. Clinically, patients with ALCL can be resistant to ALK inhibitors or relapse after treatment cessation3–5 . These data suggest that combinatorial treatment approaches are needed that inhibit potential bypass resistance pathways. Objectives: To identify bypass resistance mechanisms to ALK inhibitors in ALK-positive ALCL, and to assess combinatorial treatment strategies that pre-empt these. Design/Methods: Whole genome CRISPR activation screens (CRISPRa)6 of ALCL cell lines were performed to identify pathways that desensitise cells to ALK inhibitors. Identified pathways were validated using single gene CRISPRa, plus RT-qPCR and/or RNAseq analysis of ALK inhibitor-resistant cell lines, mouse models and patient samples, before both in vitro and in vivo assessment of novel therapeutic approaches were conducted using patient-derived xenografts (PDXs). Results: CRISPRa screens identified the growth factor receptor FGFR3 and the selenoprotein GPX4 as desensitisers to ALK inhibitors. These findings were validated in cell lines, mouse models and patient samples whereby ALK inhibitor resistant samples showed higher expression levels of these proteins. It follows that combination treatment with an ALK inhibitor and the FGFR inhibitor erdafitinib was synergistic in vitro and in vivo; for the ALK inhibitor-resistant GR-ALCL-1 PDX7 (Figure 1A), treatment with the second generation ALK inhibitor alectinib and erdafitinib overcame resistance and facilitated durable clinical and radiological (PET-CT) remission. For the ALK inhibitor-sensitive MTK PDX7 (Figure 1B), combination treatment significantly delayed relapse after treatment cessation compared to alectinib treatment alone (log-rank (Mantel-Cox) p < 0.001). Conclusion: We demonstrate actionable ALK inhibitor resistance drivers in paediatric ALCL and therapeutic strategies to overcome this. It is hoped that this will help us to move towards durable outcomes that are achieved with kinder, chemotherapy minimal regimens for children with ALK-positive ALCL. This work was supported by MUNIA/A/1685/2024. References 1. Prokoph N, Probst NA, Lee LC, Monahan JM, Matthews JD, Liang HC, et al. IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma. Blood. 2020;136:1657–1669. 2. Karaca Atabay E, Mecca C, Wang Q, Ambrogio C, Mota I, Prokoph N, et al. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma. Blood. 2022;139(5):717–731. 3. Fukano R, Mori T, Sekimizu M, Choi I, Kada A, Saito AM, Asada R, Takeuchi K, Terauchi T, Tateishi U, Horibe K, Nagai H. Alectinib for relapsed or refractory anaplastic lymphoma kinase-positive anaplastic
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