Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy
Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy
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DOI：
10.1172/jci.insight.125341
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Elkabets, Moshe
中科院分区：
文献类型：
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作者：
Badarni, Mai;Prasad, Manu;Elkabets, Moshe
AXL过表达是食管鳞状细胞癌（ESCC）和头颈部鳞状细胞癌（HNSCC）常见的抗癌耐药机制，包括对磷酸肌醇3-激酶（P13 K）的p110 n亚型特异性抑制剂BYL 719（Alpelisib）的耐药。在此，我们证明AP-1转录因子c-JUN和c-FOS调节HNSCC和ESCC中AXL的过表达。AXL和c-JUN在HNSCC患者及HNSCC和ESCC细胞系中的表达均相关。肿瘤细胞中c-JUN和c-FOS表达的沉默下调了AXL的表达，并增强了体外人乳头瘤病毒阳性（HPVPos）和阴性（HPVNeg）肿瘤细胞对BYL 719的敏感性。使用SP 600125与BYL 719组合阻断INK显示出体外协同抗增殖作用，其伴随着AXL下调和mTOR途径的有效抑制。在体内，BYL 719-SP 600125药物组合导致细胞系来源的和患者来源的异种移植物模型以及同基因头颈部小鼠癌症模型中的肿瘤生长停滞。总的来说，我们的数据表明，JNK抑制，与抗PI 3 K治疗相结合，是一种新的治疗策略，应该在HPVPos和HPVNeg HNSCC和ESCC患者中进行测试。
AXL overexpression is a common resistance mechanism to anticancer therapies, including the resistance to BYL719 (Alpelisib) - the p110n isoform specific inhibitor of phosphoinositide 3-kinase (P13K) - in esophagus squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC), However, the mechanisms underlying AXL overexpression in resistance to BYL719 remain elusive. Here, we demonstrate that the AP-1 transcription factors c-JUN and c-FOS regulate AXL overexpression in HNSCC and ESCC. The expression of AXL was correlated with that of c-JUN both in HNSCC patients and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells downregulated AXL expression and enhanced the sensitivity of human papilloma virus-positive (HPVPos) and -negative (HPVNeg) tumor cells to BYL719 in vitro. Blocking of INK using SP600125 in combination with BYL719 showed a synergistic antiproliferative effect in vitro, which was accompanied by AXL downregulation and potent inhibition of the mTOR pathway. In vivo, the BYL719-SP600125 drug combination led to the arrest of tumor growth in cell linederived and patient-derived xenograft models, as well as in syngeneic head and neck murine cancer models. Collectively, our data suggest that JNK inhibition, in combination with anti-PI3K therapy, is a new therapeutic strategy that should be tested in HPVPos and HPVNeg HNSCC and ESCC patients.