UNDERSTANDING AND OVERCOMING INNATE AND ACQUIRED MAPK-INHIBITION RESISTANCE IN ANAPLASTIC THYROID CANCER

IF 5.3 1区 医学 Q1 ONCOLOGY
Peter (Yu Fan) Zeng , Jalna Meens , Harrison Pan , Matthew Cecchini , Amir Karimi , David Palma , Eric Winquist , John Barrett , Laurie Ailles , Anthony Nichols
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引用次数: 0

Abstract

Purpose:

Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers, with some patients succumbing to the disease within weeks of diagnosis. Although a subset of patients with ATC with BRAFV600E mutation respond to the monomeric type I RAF inhibitor (RAFi) dabrafenib in combination with MEK inhibitor (MEKi) trametinib, most rapidly develop adaptive or acquired resistance. These patients, along with those who do not harbor the BRAFV600E alteration, have limited treatment options.

Materials and Methods:

To understand the mechanism of resistance to dabrafenib and trametinib, we utilized multi-region whole genome, high-coverage whole exome and single nuclei RNA-sequencing of ATC patient tumours to unravel genomic, transcriptomic, and microenvironmental evolution during type I RAFi and MEKi therapy. Cell-line and patient-derived xenograft ATC models were used to identify and understand the efficacy and mechanisms of treatment response and resistance.

Results:

Single-cell nuclei RNA sequencing of matched primary and resistant ATC patient tumours identified reactivation of the MAPK-pathway, along with immunosuppressive macrophage proliferation, underlying the development of acquired resistance. Our translational genomics led us that hypothesize that type II RAFi, which inhibit both RAF monomers and dimers, can be efficacious in overcoming treatment resistance. Screening of a panel of type II RAFi revealed that ATC cell lines are exquisitely sensitive to the type II RAFi, naporafenib, by inhibiting EphA2-mediated MAPK-signaling. We further demonstrated that naporafenib, in combination with the MEKi trametinib, can durably and robustly overcome both innate and acquired treatment resistance to dabrafenib and trametinib using ATC cell lines and patient-derived xenograft models. Finally, we describe a novel mechanism of acquired resistance to type II RAFi and MEKi through compensatory mutations in MAST1.

Conclusions:

Taken together, our work using translational and functional genomics has unraveled the differential mechanisms of treatment resistance to type I and type II RAFi in combination with trametinib and rationalizes the clinical investigation of type II RAFi in the setting of thyroid cancer.
了解和克服先天性和后天mapk抑制在间变性甲状腺癌中的抵抗
目的:间变性甲状腺癌(ATC)是最致命的人类癌症之一,一些患者在诊断后数周内死亡。尽管一部分BRAFV600E突变的ATC患者对单体I型RAF抑制剂(RAFi)达非尼联合MEK抑制剂(MEKi)曲美替尼有反应,但大多数患者迅速发展为适应性或获得性耐药。这些患者,以及那些没有BRAFV600E变异的患者,治疗选择有限。材料和方法:为了了解对达非尼和曲美替尼的耐药机制,我们利用ATC患者肿瘤的多区域全基因组、高覆盖全外显子组和单核rna测序来揭示I型RAFi和MEKi治疗期间的基因组、转录组和微环境进化。使用细胞系和患者来源的异种移植ATC模型来识别和了解治疗反应和耐药的疗效和机制。结果:匹配的原发性和耐药ATC患者肿瘤的单细胞细胞核RNA测序发现mapk通路的再激活,以及免疫抑制巨噬细胞增殖,是获得性耐药发展的基础。我们的翻译基因组学让我们假设II型RAFi,抑制RAF单体和二聚体,可以有效地克服治疗耐药性。一组II型RAFi的筛选显示,ATC细胞系通过抑制epha2介导的mapk信号传导,对II型RAFi naporafenib非常敏感。通过ATC细胞系和患者来源的异种移植模型,我们进一步证明了naporafenib与MEKi trametinib联合使用,可以持久和强大地克服对dabrafenib和trametinib的先天和获得性治疗耐药。最后,我们通过MAST1的代偿性突变描述了对II型RAFi和MEKi获得性耐药的新机制。综上所述,我们利用翻译和功能基因组学的工作揭示了曲美替尼联合治疗I型和II型RAFi耐药的不同机制,并使II型RAFi在甲状腺癌患者中的临床研究合理化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Radiotherapy and Oncology
Radiotherapy and Oncology 医学-核医学
CiteScore
10.30
自引率
10.50%
发文量
2445
审稿时长
45 days
期刊介绍: Radiotherapy and Oncology publishes papers describing original research as well as review articles. It covers areas of interest relating to radiation oncology. This includes: clinical radiotherapy, combined modality treatment, translational studies, epidemiological outcomes, imaging, dosimetry, and radiation therapy planning, experimental work in radiobiology, chemobiology, hyperthermia and tumour biology, as well as data science in radiation oncology and physics aspects relevant to oncology.Papers on more general aspects of interest to the radiation oncologist including chemotherapy, surgery and immunology are also published.
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