尽管临床进展,多发性骨髓瘤的单细胞谱显示FGFR3抑制剂的分子反应。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2023-04-01 DOI:10.1101/mcs.a006249
Danielle C Croucher, Anup Joseph Devasia, Dor D Abelman, Ali Mahdipour-Shirayeh, Zhihua Li, Natalie Erdmann, Rodger Tiedemann, Trevor J Pugh, Suzanne Trudel
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引用次数: 0

摘要

癌症的基因组特征使许多分子靶标的识别成为可能,这导致了个性化医疗的重大进步。然而,除了少数例外,精准医学方法在浆细胞恶性多发性骨髓瘤(MM)中取得的成功有限,可能是由于这种疾病的分子靶点的亚克隆性质。针对FGFR3的靶向治疗在过去十年中一直处于开发阶段,希望针对MM中异常的FGFR3活性。FGFR3激活源于约15%的MM患者中发现的复发性t(4;14)转化事件,以及该亚组中的继发性FGFR3突变。为了评估靶向FGFR3治疗MM的有效性,我们开展了一项2期临床试验,评估小分子FGFR1-4抑制剂埃尔达非替尼在伴有或不伴有FGFR3突变(NCT02952573)的复发/难治性骨髓瘤患者中的疗效。在此,我们报告了一名参与本研究的t(4;14)患者,该患者被鉴定为具有亚克隆FGFR3停止丢失缺失。尽管该个体最终在研究中取得进展并屈服于其疾病,但通过基线和单细胞基因组学治疗时对患者肿瘤的广泛分子表征,揭示了预期的分子反应。我们鉴定了fgfr3突变亚克隆在治疗后的消除和先前存在的17p染色体缺失克隆的扩增。总之,我们的研究强调了单细胞基因组学在靶向试验中的效用,因为它们可以揭示敏感性和耐药性背后的分子机制。这反过来可以指导更个性化和有针对性的治疗方法,包括那些涉及fgfr3靶向治疗的方法。
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Single-cell profiling of multiple myeloma reveals molecular response to FGFR3 inhibitor despite clinical progression.

Genomic characterization of cancer has enabled identification of numerous molecular targets, which has led to significant advances in personalized medicine. However, with few exceptions, precision medicine approaches in the plasma cell malignancy multiple myeloma (MM) have had limited success, likely owing to the subclonal nature of molecular targets in this disease. Targeted therapies against FGFR3 have been under development for the past decade in the hopes of targeting aberrant FGFR3 activity in MM. FGFR3 activation results from the recurrent transforming event of t(4;14) found in ∼15% of MM patients, as well as secondary FGFR3 mutations in this subgroup. To evaluate the effectiveness of targeting FGFR3 in MM, we undertook a phase 2 clinical trial evaluating the small-molecule FGFR1-4 inhibitor, erdafitinib, in relapsed/refractory myeloma patients with or without FGFR3 mutations (NCT02952573). Herein, we report on a single t(4;14) patient enrolled on this study who was identified to have a subclonal FGFR3 stop-loss deletion. Although this individual eventually progressed on study and succumbed to their disease, the intended molecular response was revealed through an extensive molecular characterization of the patient's tumor at baseline and on treatment using single-cell genomics. We identified elimination of the FGFR3-mutant subclone after treatment and expansion of a preexisting clone with loss of Chromosome 17p. Altogether, our study highlights the utility of single-cell genomics in targeted trials as they can reveal molecular mechanisms that underlie sensitivity and resistance. This in turn can guide more personalized and targeted therapeutic approaches, including those that involve FGFR3-targeting therapies.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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