A Fusion Transcription Factor-Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target.
A Fusion Transcription Factor-Driven Cancer Progresses to a Fusion-Independent Relapse via Constitutive Activation of a Downstream Transcriptional Target.
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DOI：
10.1158/0008-5472.can-20-1613
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Barr FG
中科院分区：
文献类型：
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作者：
Boudjadi S;Pandey PR;Chatterjee B;Nguyen TH;Sun W;Barr FG
靶向单药治疗通常会失败，因为一个亚组的细胞会产生耐药性，演变成复发性肿瘤。腺泡状横纹肌肉瘤是一种侵袭性肌源性软组织癌，与编码新型融合转录因子的特征性PAX 3-FOXO 1基因融合相关。在我们的PAX 3-FOXO 1诱导的横纹肌肉瘤成肌细胞模型中，PAX 3-FOXO 1的去诱导模拟了拮抗融合癌蛋白的靶向治疗。这种模拟治疗最初导致原发性肿瘤消退，但PAX 3-FOXO 1非依赖性复发肿瘤最终在延迟后形成。我们在这里报告，成纤维细胞生长因子FGF 8的上调，PAX 3-FOXO 1的直接转录靶点，是负责PAX 3-FOXO 1非依赖性肿瘤复发的机制。作为PAX 3-FOXO 1的转录靶点，FGF 8促进了在成肌细胞系统中发展的表达PAX 3-FOXO 1的原发性肿瘤的致癌活性。在PAX 3-FOXO 1去诱导后形成的复发性肿瘤中，FGF 8表达是必要的，并且足以通过自分泌机制诱导PAX 3-FOXO 1非依赖性肿瘤生长。FGF 8也在表达人PAX 3-FOXO 1的横纹肌肉瘤细胞系中表达，并有助于增殖和转化。在PAX 3-FOXO 1表达降低的人横纹肌肉瘤细胞系中，FGF 8上调挽救了致瘤性，并模拟了PAX 3-FOXO 1靶向治疗后的复发。我们提出，PAX 3-FOXO 1转录靶点的表达失调可以产生针对这种致癌转录因子的治疗抗性，并假设这种抗性机制最终可能被拮抗相应下游途径的治疗方法所抵消。
Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1-induced rhabdomyosarcoma, de-induction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1-independent recurrent tumors eventually form after a delay. We report here that upregulation of the fibroblast growth factor FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1-independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1-expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 de-induction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1-independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1-expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1-targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.