Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, Maryland.
Cancer Res. 2021 Jun 1;81(11):2930-2942. doi: 10.1158/0008-5472.CAN-20-1613. Epub 2021 Feb 15.
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 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1-induced rhabdomyosarcoma, deinduction 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 , 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 deinduction, 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. SIGNIFICANCE: In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.
靶向单药治疗通常会失败，因为一小部分细胞会产生耐药性，进而发展为复发性肿瘤。肺泡横纹肌肉瘤是一种侵袭性的肌源性软组织癌，与一种特征性的基因融合有关，该融合基因编码一种新型融合转录因子。在我们的 PAX3-FOXO1 诱导的横纹肌肉瘤成肌细胞模型中，PAX3-FOXO1 的去诱导模拟了一种针对融合致癌蛋白的靶向治疗。这种模拟治疗最初导致原发性肿瘤消退，但在延迟后，PAX3-FOXO1 非依赖性复发性肿瘤最终形成。我们在这里报告，直接转录靶标上调，是 PAX3-FOXO1 非依赖性肿瘤复发的一种机制。作为 PAX3-FOXO1 的转录靶标，FGF8 促进了在成肌细胞系统中发育的 PAX3-FOXO1 表达的原发性肿瘤中的致癌活性。在 PAX3-FOXO1 去诱导后形成的复发性肿瘤中，FGF8 表达是通过自分泌机制诱导 PAX3-FOXO1 非依赖性肿瘤生长所必需和充分的。FGF8 也在人 PAX3-FOXO1 表达的横纹肌肉瘤细胞系中表达，并促进增殖和转化。在 PAX3-FOXO1 表达降低的人横纹肌肉瘤细胞系中，FGF8 的上调挽救了致癌性，并在 PAX3-FOXO1 靶向治疗后模拟了复发。我们提出，PAX3-FOXO1 转录靶标的失调表达可产生对针对这种致癌转录因子的治疗的耐药性，并假设这种耐药机制最终可能通过拮抗相应下游途径的治疗方法来对抗。意义：在由融合转录因子引发的癌症模型中，下游转录靶标的组成性激活导致融合致癌蛋白非依赖性复发，从而突出了一种新的进展机制和治疗靶标。
