Koinis Filippos, Corn Paul, Parikh Nila, Song Jian, Vardaki Ioulia, Mourkioti Ioanna, Lin Sue-Hwa, Logothetis Christopher, Panaretakis Theocharis, Gallick Gary
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2020 Jan 19;12(1):244. doi: 10.3390/cancers12010244.
The overall goal of this study was to elucidate the role of FGFR1 induction in acquired resistance to MET and VEGFR2 inhibition by cabozantinib in prostate cancer (PCa) and leverage this understanding to improve therapy outcomes. The response to cabozantinib was examined in mice bearing patient-derived xenografts in which FGFR1 was overexpressed. Using a variety of cell models that reflect different PCa disease states, the mechanism underpinning FGFR1 signaling activation by cabozantinib was investigated. We performed parallel investigations in specimens from cabozantinib-treated patients to confirm our in vitro and in vivo data. FGFR1 overexpression was sufficient to confer resistance to cabozantinib. Our results demonstrate transcriptional activation of FGF/FGFR1 expression in cabozantinib-resistant models. Further analysis of molecular pathways identified a YAP/TBX5-driven mechanism of FGFR1 and FGF overexpression induced by MET inhibition. Importantly, knockdown of YAP and TBX5 led to decreased FGFR1 protein expression and decreased mRNA levels of FGFR1, FGF1, and FGF2. This association was confirmed in a cohort of hormone-naïve patients with PCa receiving androgen deprivation therapy and cabozantinib, further validating our findings. These findings reveal that the molecular basis of resistance to MET inhibition in PCa is FGFR1 activation through a YAP/TBX5-dependent mechanism. YAP and its downstream target TBX5 represent a crucial mediator in acquired resistance to MET inhibitors. Thus, our studies provide insight into the mechanism of acquired resistance and will guide future development of clinical trials with MET inhibitors.
本研究的总体目标是阐明FGFR1诱导在前列腺癌（PCa）中对卡博替尼介导的MET和VEGFR2抑制产生获得性耐药中的作用，并利用这一认识改善治疗效果。在FGFR1过表达的患者来源异种移植小鼠中检测了对卡博替尼的反应。使用反映不同PCa疾病状态的多种细胞模型，研究了卡博替尼激活FGFR1信号传导的机制。我们对接受卡博替尼治疗的患者的标本进行了平行研究，以证实我们的体外和体内数据。FGFR1过表达足以赋予对卡博替尼的耐药性。我们的结果表明，在卡博替尼耐药模型中FGF/FGFR1表达的转录激活。对分子途径的进一步分析确定了一种由MET抑制诱导的YAP/TBX5驱动的FGFR1和FGF过表达机制。重要的是，敲低YAP和TBX5导致FGFR1蛋白表达降低以及FGFR1、FGF1和FGF2的mRNA水平降低。在一组接受雄激素剥夺治疗和卡博替尼的激素初治PCa患者中证实了这种关联，进一步验证了我们的发现。这些发现揭示了PCa中对MET抑制耐药的分子基础是通过YAP/TBX5依赖性机制激活FGFR1。YAP及其下游靶点TBX5是对MET抑制剂获得性耐药的关键介质。因此，我们的研究为获得性耐药机制提供了见解，并将指导未来MET抑制剂的临床试验开发。
