Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Nat Med. 2019 Jan;25(1):119-129. doi: 10.1038/s41591-018-0243-z. Epub 2018 Nov 19.
Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
伊布替尼联合维奈托克在套细胞淋巴瘤中具有高度疗效。然而，需要制定评估治疗反应的策略。我们在 AIM 研究中对患者进行的前瞻性分析揭示了明确区分应答者和无应答者的基因组特征。在大多数获得完全缓解的患者中存在 ATM 突变，而在原发性耐药的所有患者和三分之二的复发疾病患者中存在染色体 9p21.1-p24.3 缺失和/或 SWI-SNF 染色质重塑复合物的成分突变。循环肿瘤 DNA 分析显示，这些改变可以进行动态监测，提供关于治疗反应和肿瘤演变的并发信息。功能建模表明，SWI-SNF 复合物的缺陷促进了 BCL2L1（Bcl-xL）的转录上调，为伊布替尼联合维奈托克提供了选择性优势。这些数据共同强调了对治疗反应分子基础的重要见解，并为实时评估创新靶向治疗提供了模型。
