Newly Identified Members of FGFR1 Splice Variants Engage in Cross-talk with AXL/AKT Axis in Salivary Adenoid Cystic Carcinoma
Newly Identified Members of FGFR1 Splice Variants Engage in Cross-talk with AXL/AKT Axis in Salivary Adenoid Cystic Carcinoma
复制标题
DOI：
10.1158/0008-5472.can-20-1780
复制
发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
Ha，Patrick K.
中科院分区：
文献类型：
--
作者：
Humtsoe，Joseph O.;Kim，Hyun-Su;Ha，Patrick K.
腺样囊性癌（ACC）是唾液腺第二常见的恶性肿瘤。虽然其特征为惰性肿瘤，但ACC常导致无法治愈的转移性疾病。ACC患者对目前可用的治疗药物反应不佳，导致反应有限的因素尚不清楚。确定ACC中经常发生的分子改变的作用可能会澄清ACC的肿瘤发生，并促进有效治疗策略的发展。通过对原发ACC肿瘤和匹配的正常唾液腺组织的RNA测序进行剪接表达变异分析和离群统计，我们发现了ACC特异性基因的多个选择性剪接事件（ASE）。在ACC细胞和患者来源的异种移植物中，fgfr1是唯一表达的ASE。详细的PCR分析鉴定出三种新的、截断的、细胞内结构域缺失的fgfr1变异体（FGFR1v）。克隆和表达分析表明，这三种FGFR1v是细胞表面蛋白，FGFR1v的表达增强了pAKT活性，并且细胞对药物FGFR1抑制剂具有更强的抗性。FGFR1v诱导的AKT活化与AXL功能相关，FGFR1v敲低细胞中AXL活性的抑制导致ACC细胞毒性增强。此外，在ACC细胞中，AXL和FGFR1的双重抑制增加了细胞杀伤作用。这项研究表明，这些先前描述的FGFR1v与AXL合作，使细胞对FGFR1抑制剂脱敏，这支持了进一步研究FGFR1和AXL联合抑制作为有效的ACC治疗方法。本研究发现了几个FGFR1变体，它们通过独立于FGF/FGFR1的AXL/AKT信号通路起作用，使细胞对FGFR1抑制剂脱敏，提示ACC的潜在耐药机制。本研究发现了几个FGFR1变体，它们通过独立于FGF/FGFR1的AXL/AKT信号通路起作用，使细胞对FGFR1抑制剂脱敏，提示ACC的潜在耐药机制。
Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis and outlier statistics on RNA sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC. In ACC cells and patient-derived xenografts,FGFR1was a uniquely expressed ASE. Detailed PCR analysis identified three novel, truncated, intracellular domain-lackingFGFR1variants (FGFR1v). Cloning and expression analysis suggest that the three FGFR1v are cell surface proteins, that expression of FGFR1v augmented pAKT activity, and that cells became more resistant to pharmacologic FGFR1 inhibitor. FGFR1v-induced AKT activation was associated with AXL function, and inhibition of AXL activity in FGFR1v knockdown cells led to enhanced cytotoxicity in ACC. Moreover, cell killing effect was increased by dual inhibition of AXL and FGFR1 in ACC cells. This study demonstrates that these previously undescribed FGFR1v cooperate with AXL and desensitize cells to FGFR1 inhibitor, which supports further investigation into combined FGFR1 and AXL inhibition as an effective ACC therapy.This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor suggestive of a potential resistance mechanism in ACC.SignificanceThis study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor, suggestive of a potential resistance mechanism in ACC.